Publications

INTRODUCTION

Intra-isthmus reentry (IIR) is a circuit within the cavotricuspid isthmus (CTI). The purpose of this study is to prospectively define the electrogram and surface ECG characteristics of IIR, and its clinical implications.

METHODS AND RESULTS

Fourteen patients underwent electrophysiological studies and were found to have IIR. Detailed electrogram mapping of the CTI was available in all, electroanatomic mapping (EAM) in 8 of 14 (57%) patients. In all, entrainment mapping during tachycardia proved reentry, and showed that the anteroinferior CTI was out of the circuit and the septal CTI was in the circuit in 12 of 14 patients, whereas in 2, the circuit was confined within the mid and/or anteroinferior CTI. Fractionated potentials (FPs) spanning 34-71% of the tachycardia cycle length were recorded within the CTI in all, and double potentials were inscribed in 10 of 14 (71%). Analysis of the tricuspid annulus electrograms showed spontaneous shifts from a counterclockwise (CCW) to clockwise or fusion patterns. Surface ECGs showed either typical CCW pattern (12 patients) or atypical patterns (3 patients). The EAMs showed a focal pattern in 3, a CCW pattern in 5. The successful ablation site always occurred at the area with maximal FP duration. Over the same period, 33 of 384 (9%) patients who underwent ablation for CTI-dependent flutter had prior successful CTI ablation, 7 of 33 (21%) were found to have IIR during the redo procedure.

CONCLUSIONS

(1) Electrogram and ECG patterns of IIR frequently show atypical flutter. (2) IIR was successfully ablated in an area of the CTI associated with maximal duration of FPs. (3) IIR is a significant cause of "recurrent flutter" in patients with prior CTI ablation.

BACKGROUND

Hepatic steatosis is common in persons with HIV and hepatitis C virus (HCV); yet biopsy measurement of steatosis is prone to sampling error. We compared magnetic resonance spectroscopy (MRS) measurement of steatosis to histology in HIV/HCV-coinfected patients and explored the associated adipose tissue and metabolic factors.

METHODS

Cross-sectional analysis of 42 HIV/HCV-coinfected men and women. Logistic regression analysis identified factors (MRI-measured visceral adipose tissue and abdominal subcutaneous adipose tissue and Homeostasis Model Assessment-estimated insulin resistance) associated with histologic steatosis (≥ 5% of hepatocytes with fat) and MRS steatosis (≥ 5% of hepatic fat).

RESULTS

MRS steatosis was strongly associated with histologic steatosis, when measured continuously (odds ratio: 10.2 per doubling of MRS-measured hepatic fat; 95% confidence interval: 2.9 to 69.3) and dichotomously (Kappa coefficient = 0.52; P = 0.0007). Four of the 10 with MRS-measured steatosis did not have histologic steatosis; 3 of 9 with histologic steatosis did not have MRS-measured steatosis (67% sensitivity; 88% specificity). Associations of visceral adipose tissue and abdominal subcutaneous adipose tissue were associated with both histologic and MRS-measured steatosis. Insulin resistance was also associated with both.

CONCLUSIONS

When compared with histology, MRS was similarly associated with adipose tissue and metabolic factors. MRS is a useful noninvasive alternative to biopsy in HIV/HCV coinfection.

Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are highly efficacious antimalarial therapies in Africa. However, there are limited data regarding the tolerability of these drugs in young children. We used data from a randomized control trial in rural Uganda to compare the risk of early vomiting (within one hour of dosing) for children 6-24 months of age randomized to receive DP (n = 240) or AL (n = 228) for treatment of uncomplicated malaria. Overall, DP was associated with a higher risk of early vomiting than AL (15.1% versus 7.1%; P = 0.007). The increased risk of early vomiting with DP was only present among breastfeeding children (relative risk [RR] = 3.35, P = 0.001) compared with children who were not breastfeeding (RR = 1.03, P = 0.94). Age less than 18 months was a risk factor for early vomiting independent of treatment (RR = 3.27, P = 0.02). Our findings indicate that AL may be better tolerated than DP among young breastfeeding children treated for uncomplicated malaria.

BACKGROUND

Early cessation of breastfeeding increases morbidity and mortality of children born to HIV-infected mothers in resource-limited settings. However, data on whether breastfeeding reduces the risk of malaria in HIV-exposed and HIV-infected children is limited.

METHODS

We prospectively followed 99 HIV-unexposed children, 202 HIV-exposed children, and 45 HIV-infected children in a high malaria transmission area in Uganda. All children were given insecticide-treated bednets. HIV-exposed and HIV-infected children were given trimethoprim-sulfamethoxazole prophylaxis. Malaria diagnosis was based on fever and a positive blood smear. Date of breastfeeding cessation was determined through monthly questionnaires. Associations between breastfeeding and the risk of malaria were modeled through binomial generalized estimating equations using multivariate analysis adjusting for repeated measures, age, and location of residence. Analyses were stratified according to mothers' and children's HIV status.

RESULTS

Breastfeeding was associated with a significantly lower risk of malaria in 6-15 months old HIV-exposed children (relative risk [RR] = 0.62; P = 0.008) and 6-15 months old HIV-infected children (RR = 0.31; P = 0.002). However, breastfeeding was not protective against malaria for >15-24 months old HIV-unexposed (RR = 1.14; P = 0.21) or >15-24 months old HIV-infected children (RR = 1.11; P = 0.75).

CONCLUSIONS

HIV-infected mothers should be counseled about the importance of breastfeeding and trimethoprim-sulfamethoxazole prophylaxis to protect their young children and themselves against malaria.

BACKGROUND

The human immunodeficiency virus (HIV) alters the presentation of pulmonary tuberculosis (PTB), but it remains unclear whether alterations occur at a CD4 cell threshold or throughout HIV infection.

OBJECTIVE

To better understand the relationship between CD4 count and clinical and radiographic presentation of PTB.

SETTING AND DESIGN

Initial presentations of culture-confirmed PTB patients evaluated at a Ugandan national TB referral center and an affiliated research unit were compared by HIV status and across 11 CD4 cell count strata: 0-50 to >500 cells/μl.

RESULTS

A total of 873 HIV-infected PTB cases were identified. Among HIV-infected PTB cases with CD4 < 50, 21% had a normal chest X-ray (CXR) vs. 2% with CD4 > 500, with a continuous trend across CD4 strata (test for trend, P < 0.001). All radiographic manifestations of PTB displayed significant trends across CD4 strata. HIV-infected vs. non-HIV-infected patients had no significant difference in CXR findings of miliary patterns or pleural effusion at CD4 > 100, normal CXR or fibrosis at CD4 > 150, adenopathy at CD4 > 250, and cavitation or upper lung disease at CD4 > 300. Twenty-three per cent of co-infected cases with CD4 < 50 and 1% with CD4 > 500 had negative acid-fast bacilli (AFB) smears, with a significant trend between (P < 0.001).

CONCLUSION

Variations in CXR appearance and AFB smear correlate with CD4 decline in significant, continuous trends.

BACKGROUND

In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease remains a predictor of death after HAART initiation.

METHODS

To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women's Interagency HIV Study. Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.

RESULTS

Chronic kidney disease (estimated glomerular filtration rate less than 60 mL/min/1.73 m) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history, and CD4 cell count (hazard ratio 2.23, 95% confidence interval: 1.45-3.43). Adjustment for hypertension and diabetes history attenuated this association (hazard ratio = 1.89, confidence interval: 0.94-3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (hazard ratio = 1.09, confidence interval: 1.00-1.19, per 20% decrease in estimated glomerular filtration rate).

CONCLUSIONS

Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with chronic kidney disease in HIV-infected persons.

Cathepsin G is a major secreted serine peptidase of neutrophils and mast cells. Studies in Ctsg-null mice suggest that cathepsin G supports antimicrobial defenses but can injure host tissues. The human enzyme has an unusual "Janus-faced" ability to cleave peptides at basic (tryptic) as well as aromatic (chymotryptic) sites. Tryptic activity has been attributed to acidic Glu(226) in the primary specificity pocket and underlies proposed important functions, such as activation of prourokinase. However, most mammals, including mice, substitute Ala(226) for Glu(226), suggesting that human tryptic activity may be anomalous. To test this hypothesis, human cathepsin G was compared with mouse wild-type and humanized active site mutants, revealing that mouse primary specificity is markedly narrower than that of human cathepsin G, with much greater Tyr activity and selectivity and near absence of tryptic activity. It also differs from human in resisting tryptic peptidase inhibitors (e.g., aprotinin), while favoring angiotensin destruction at Tyr(4) over activation at Phe(8). Ala(226)Glu mutants of mouse cathepsin G acquire tryptic activity and human ability to activate prourokinase. Phylogenetic analysis reveals that the Ala(226)Glu missense mutation appearing in primates 31-43 million years ago represented an apparently unprecedented way to create tryptic activity in a serine peptidase. We propose that tryptic activity is not an attribute of ancestral mammalian cathepsin G, which was primarily chymotryptic, and that primate-selective broadening of specificity opposed the general trend of increased specialization by immune peptidases and allowed acquisition of new functions.

BACKGROUND

Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response.

OBJECTIVES

To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores.

METHODS

Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n = 71, and Fresno Non Asthmatic Group, n = 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n = 40, and Stanford Non Asthmatic Group, n = 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score.

RESULTS

Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P ≤ .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P ≤ .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P ≤ .05).

CONCLUSION

Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.

OBJECTIVE

To compare signalment of horses with cervical vertebral malformation-malarticulation (CVM) with that of control horses and to describe results of clinical examination, diagnostic imaging and necropsy findings, and reported outcome in horses with CVM.

DESIGN

Retrospective case-control study.

ANIMALS

270 horses with CVM and 608 control horses admitted to 6 veterinary hospitals from 1992 through 2007.

PROCEDURES

Medical records of participating hospitals were reviewed to identify horses with CVM (ie, case horses) and contemporaneous control (non-CVM-affected) horses that were admitted for treatment. Signalment was compared between case horses and control horses. Results of clinical examination, laboratory and diagnostic imaging findings, necropsy results, and outcome were assessed for horses with CVM.

RESULTS

Case horses were younger (median age, 2 years) than were control horses (median age, 7 years). Thoroughbreds, warmbloods, and Tennessee Walking Horses were overrepresented in the CVM group. Gait asymmetry and cervical hyperesthesia were frequently detected in horses with CVM. Vertebral canal stenosis and articular process osteophytosis were commonly observed at necropsy; agreement between the results of radiographic or myelographic analysis and detection of lesions at necropsy was 65% to 71% and 67% to 78%, respectively. Of 263 horses with CVM for which outcome was recorded, 1 died and 172 (65.4%) were euthanatized.

CONCLUSIONS AND CLINICAL RELEVANCE

Odds of a diagnosis of CVM were greater in young horses and horses of specific breeds. Detection of gait asymmetry and cervical hyperesthesia were frequently reported in association with CVM. Accurate diagnosis of lesions associated with CVM by use of radiography and myelography can be challenging.

BACKGROUND

Understanding the effects of interactions between multiple genes and asthma medications may aid in the understanding of the heterogeneous response to asthma therapies.

OBJECTIVE

To identify modulating effects of arachidonate 5-lipoxygenase-activating protein (ALOX5AP) and leukotriene A(4) hydrolase (LTA4H) gene polymorphisms on the drug-drug interaction between leukotriene modifiers and albuterol in Mexicans and Puerto Ricans.

METHODS

In a cross-sectional study of 293 Mexicans and 356 Puerto Ricans with asthma, ALOX5AP and LTA4H genes were sequenced, and interactions between gene polymorphisms and bronchodilator responsiveness to albuterol were compared between leukotriene modifier users and nonusers.

RESULTS

In heterozygotes and homozygotes for the minor allele at LTA4H single nucleotide polymorphism (SNP) rs2540491 and heterozygotes for the major allele at LTA4H SNP rs2540487, leukotriene modifier use was associated with a clinically significant increase in percent change in FEV(1) after albuterol administration of 7.10% (P = .002), 10.06% (P = .001), and 10.03% (P < .001), respectively. Presence of the major allele at ALOX5AP SNP rs10507391 or the minor allele at ALOX5AP SNP rs9551963 augmented this response. When stratified by ethnicity, these findings held true for Puerto Ricans but not Mexicans.

CONCLUSION

LTA4H and ALOX5AP gene polymorphisms modify the augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Ricans but not Mexicans with asthma.