Publications

PURPOSE OF REVIEW

Cocaine use is associated with several rheumatic syndromes. This review summarizes these clinical manifestations and highlights recent developments linked to levamisole-adulterated cocaine.

RECENT FINDINGS

Cocaine use has been linked to several distinctive syndromes that can be difficult to distinguish from idiopathic rheumatic diseases. These disorders can range in severity from purely cosmetic damage to organ and/or life-threatening disease that includes sinonasal destruction and vasculitis. Many of these illnesses are associated with antineutrophil cytoplasmic antibodies (cytoplasmic, perinuclear and atypical perinuclear patterns). With the recent introduction of levamisole as a cocaine adulterant, a newly reported syndrome has emerged that is associated with neutropenia, retiform purpura with cutaneous necrosis and autoantibodies consisting of high-titre perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) with specificities for 'atypical' antigens.

SUMMARY

Cocaine use is associated with clinical syndromes that closely mimic other primary rheumatic diseases. Given the high prevalence of cocaine use and its adulteration with levamisole, clinicians should be familiar with these rheumatic manifestations in order to avoid misdiagnosis and unnecessary treatment with potentially toxic therapies.

INTRODUCTION

Our objective was to determine rheumatoid arthritis (RA) patients' understanding of methotrexate and assess whether knowledge varies by age, education, English language proficiency, or other disease-related factors.

METHODS

Adults with RA (n = 135) who were enrollees of an observational cohort completed a structured telephone interview in their preferred language between August 2007 and July 2009. All subjects who reported taking methotrexate were asked 11 questions about the medication in addition to demographics, education level, and language proficiency. Primary outcome was a total score below the 50th percentile (considered inadequate methotrexate knowledge). Bivariable and multivariable logistic regressions were performed. Covariates included demographics, language proficiency, education, and disease characteristics.

RESULTS

Of 135 subjects, 83% were female, with a mean age of 55 ± 14 years. The majority spoke English (64%), followed by 22% Spanish and 14% Cantonese or Mandarin. Limited English language proficiency (LEP) was reported in 42%. Mean methotrexate knowledge score was 5.4 ± 2.6 (range, 0 to 10); 73 (54%) had a score lower than 5 (of 10). Age older than 55, less than high school education, LEP, better function, and biologic use were independently associated with poor knowledge.

CONCLUSIONS

In a diverse RA cohort, overall methotrexate knowledge was poor. Older age and limited proficiency in English were significant correlates of poor knowledge. Identification of language barriers and improved clinician-patient communication around methotrexate dosing and side effects may lead to improved safety and enhanced benefits of this commonly used RA medication.

Antiretroviral therapy has revolutionized the course of HIV infection, improving immune function and decreasing dramatically the mortality and morbidity due to the opportunistic complications of the disease. Nonetheless, even with sustained suppression of HIV replication, many HIV-infected persons experience a syndrome characterized by increased T cell activation and evidence of heightened inflammation and coagulation. This residual immune dysregulation syndrome or RIDS is more common in persons who fail to increase circulating CD4+ T cells to normal levels and in several epidemiologic studies it has been associated with increased morbidity and mortality. These morbid and fatal events are not the typical opportunistic infections and malignancies seen in the early AIDS era but rather comprise a spectrum of cardiovascular events, liver disease, metabolic disorders, kidney disease, bone disease, and a spectrum of malignant complications distinguishable from the opportunistic malignancies that characterized the earlier days of the AIDS epidemic. While immune activation, inflammation, and coagulopathy are characteristic of untreated HIV infection and improve with drug-induced control of HIV replication, the drivers of RIDS in treated HIV infection are incompletely understood. And while inflammation, immune activation, and coagulopathy are more common in treated persons who fail to restore circulating CD4+ T cells, it is not entirely clear how these two phenomena are linked.

Traditional healer and/or spiritual counselor (TH/SC) use has been associated with delays in HIV testing. We examined HIV-infected individuals in southwestern Uganda to test the hypothesis that TH/SC use was also associated with lower CD4 counts at antiretroviral therapy (ART) initiation. Approximately 450 individuals initiating ART through an HIV/AIDS clinic at the Mbarara University of Science and Technology (MUST) were recruited to participate. Patients were predominantly female, ranged in age from 18 to 75, and had a median CD4 count of 130. TH/SC use was not associated with lower CD4 cell count, but age and quality-of-life physical health summary score were associated with CD4 cell count at initiation while asset index was negatively associated with CD4 count at ART initiation. These findings suggest that TH/SC use does not delay initiation of ART.

HIV infection remains highly stigmatized throughout sub-Saharan Africa despite the increasing availability of treatment. HIV-related stigma is commonly described to be highly prevalent in East Africa, but none of these studies have employed validated scales for measurement. We used data from 456 people living with HIV/AIDS in rural Uganda to validate the six-item Internalized AIDS-Related Stigma Scale. The scale demonstrated acceptable internal consistency (Cronbach's alpha = 0.73) and time stability. Exploratory factor analysis indicated the presence of a single factor. Construct validity was supported by observations that the scale was correlated with related constructs such as depression and mental health-related quality of life. The scale was able to discriminate between groups of persons who were different in terms of treatment status and their experience of HIV-related self-blame. Taken together, these findings suggest that the Internalized AIDS-Related Stigma Scale may be a useful tool for socio-behavioral HIV research.

Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.

The hydrodynamic tail vein injection is a technique that is used to deliver nucleic acids into live mice. Delivery through this method results in the in vivo transfection of foreign DNA primarily in the liver. Here, we describe the use of this technique to test for regulatory activity of liver promoters and enhancers, using a dual luciferase reporter system as the readable/measureable output and how this application can be used for pharmacogenomic studies.

BACKGROUND

Gene expression is controlled by proximal promoters and distal regulatory elements such as enhancers. While the activity of some promoters can be invariant across tissues, enhancers tend to be highly tissue-specific.

RESULTS

We compiled sets of tissue-specific promoters based on gene expression profiles of 79 human tissues and cell types. Putative transcription factor binding sites within each set of sequences were used to train a support vector machine classifier capable of distinguishing tissue-specific promoters from control sequences. We obtained reliable classifiers for 92% of the tissues, with an area under the receiver operating characteristic curve between 60% (for subthalamic nucleus promoters) and 98% (for heart promoters). We next used these classifiers to identify tissue-specific enhancers, scanning distal non-coding sequences in the loci of the 200 most highly and lowly expressed genes. Thirty percent of reliable classifiers produced consistent enhancer predictions, with significantly higher densities in the loci of the most highly expressed compared to lowly expressed genes. Liver enhancer predictions were assessed in vivo using the hydrodynamic tail vein injection assay. Fifty-eight percent of the predictions yielded significant enhancer activity in the mouse liver, whereas a control set of five sequences was completely negative.

CONCLUSIONS

We conclude that promoters of tissue-specific genes often contain unambiguous tissue-specific signatures that can be learned and used for the de novo prediction of enhancers.