Publications

The essential transactivator function of the HIV Tat protein is regulated by multiple posttranslational modifications. Although individual modifications are well characterized, their crosstalk and dynamics of occurrence during the HIV transcription cycle remain unclear.We examine interactions between two critical modifications within the RNA-binding domain of Tat: monomethylation of lysine 51 (K51) mediated by Set7/9/KMT7, an early event in the Tat transactivation cycle that strengthens the interaction of Tat with TAR RNA, and acetylation of lysine 50 (K50) mediated by p300/KAT3B, a later process that dissociates the complex formed by Tat, TAR RNA and the cyclin T1 subunit of the positive transcription elongation factor b (P-TEFb). We find K51 monomethylation inhibited in synthetic Tat peptides carrying an acetyl group at K50 while acetylation can occur in methylated peptides, albeit at a reduced rate. To examine whether Tat is subject to sequential monomethylation and acetylation in cells, we performed mass spectrometry on immunoprecipitated Tat proteins and generated new modification-specific Tat antibodies against monomethylated/acetylated Tat. No bimodified Tat protein was detected in cells pointing to a demethylation step during the Tat transactivation cycle. We identify lysine-specific demethylase 1 (LSD1/KDM1) as a Tat K51-specific demethylase, which is required for the activation of HIV transcription in latently infected T cells. LSD1/KDM1 and its cofactor CoREST associates with the HIV promoter in vivo and activate Tat transcriptional activity in a K51-dependent manner. In addition, small hairpin RNAs directed against LSD1/KDM1 or inhibition of its activity with the monoamine oxidase inhibitor phenelzine suppresses the activation of HIV transcription in latently infected T cells.Our data support the model that a LSD1/KDM1/CoREST complex, normally known as a transcriptional suppressor, acts as a novel activator of HIV transcription through demethylation of K51 in Tat. Small molecule inhibitors of LSD1/KDM1 show therapeutic promise by enforcing HIV latency in infected T cells.

BACKGROUND

The study was conducted to evaluate the impact of out-of-pocket expense on intrauterine device (IUD) utilization among women with private insurance.

STUDY DESIGN

We reviewed the records of all women with private insurance who requested an IUD for contraception from an urban academic gynecology practice from May 2007 through April 2008. For each patient, we determined the out-of-pocket expense that would be incurred and whether she ultimately had an IUD placed. The total charge for placement of a copper or levonorgestrel IUD (including the device) was $815.

RESULTS

Ninety-five women requested an IUD during the study period. The distribution of out-of-pocket expense was bimodal: less than $50 for 35 (37%) women and greater than $500 for 52 (55%) women. Intrauterine device insertion occurred in 24 (25%) women, 19 of whom had an out-of-pocket expense less than $50. In univariate and multivariable analysis, women with insurance coverage that resulted in less than $50 out-of-pocket expense for the IUD were more likely to have an IUD placed than women required to pay $50 or more (adjusted odds ratio=11.4, 95% confidence interval=3.6-36.6).

CONCLUSIONS

Women requesting an IUD for contraception are significantly more likely to have an IUD placed when out-of-pocket expense is less than $50.

BACKGROUND

The need to ask a clinician to remove an intrauterine contraceptive (IUC) may deter some women from trying the method. There is little risk to a woman who attempts to remove her own IUC.

STUDY DESIGN

In 2010, 602 women seeking abortion completed a computerized survey in the waiting rooms of six US abortion clinics. The survey asked women to rate their interest in using the currently available IUCs and a hypothetical "new" self-removable IUC.

RESULTS

Overall, 25% of respondents would be more willing to try an IUC if they could remove it themselves. Interest in a self-removable IUC was higher among women who were already considering use of an IUC. After controlling for multiple covariates, women who were likely to have unprotected sex in the future were more willing to consider use of an IUC if they had the option of self-removal (odds ratio 1.63, 95% confidence interval 1.03-2.59).

CONCLUSIONS

Informing women that they may safely attempt self-removal of their IUC may increase interest in trying an IUC.

BACKGROUND

Physician-directed pharmaceutical advertising is regulated in the United States by the Food and Drug Administration (FDA); adherence to current FDA guidelines is unknown. Our objective was to determine adherence rates of physician-directed print advertisements in biomedical journals to FDA guidelines and describe content important for safe prescribing.

METHODS AND FINDINGS

Cross-sectional analysis of November 2008 pharmaceutical advertisements within top U.S.-based biomedical journals publishing original research. We excluded advertisements for devices, over the counter medications, and disease awareness. We utilized FDA guideline items identifying unique forms of advertisement bias to categorize advertisements as adherent to FDA guidelines, possibly non-adherent to at least 1 item, or non-adherent to at least 1 item. We also evaluated advertisement content important for safe prescribing, including benefit quantification, risk information and verifiable references. All advertisements were evaluated by 2 or more investigators, with differences resolved by discussion. Twelve journals met inclusion criteria. Nine contained pharmaceutical advertisements, including 192 advertisements for 82 unique products; median 2 per product (range 1-14). Six "teaser" advertisements presented only drug names, leaving 83 full unique advertisements. Fifteen advertisements (18.1%) adhered to all FDA guidelines, 41 (49.4%) were non-adherent with at least one form of FDA-described bias, and 27 (32.5%) were possibly non-adherent due to incomplete information. Content important for safe prescribing was often incomplete; 57.8% of advertisements did not quantify serious risks, 48.2% lacked verifiable references and 28.9% failed to present adequate efficacy quantification. Study limitations included its focus on advertisements from a single month, the subjectivity of FDA guidelines themselves, and the necessary subjectivity of determinations of adherence.

CONCLUSIONS

Few physician-directed print pharmaceutical advertisements adhere to all FDA guidelines; over half fail to quantify serious risks. The FDA could better protect public health by creating new more objective advertisement guidelines requiring transparent presentation of basic safety and efficacy information.

UNLABELLED

The metabolic syndrome affects 25% of the U.S. population and greatly increases the risk of diabetes and coronary artery disease (CAD). We tested the hypothesis that the metabolic syndrome is associated with impaired coronary vasodilator function, a marker of atherosclerotic disease activity.

METHODS

Four hundred sixty-two patients at risk for CAD, as defined by a low-density lipoprotein cholesterol ≥ 160 mg/dL with fewer than 2 coronary risk factors, a low-density lipoprotein cholesterol ≥ 130 mg/dL with 2 or more coronary risk factors, or with documented CAD were included. A subset of 234 individuals underwent repeated PET at 1 y. Myocardial blood flow (MBF) and vasodilator reserve were assessed by PET. Modified criteria of the National Cholesterol Education Program, Adult Treatment Panel III were used to characterize the metabolic syndrome.

RESULTS

Adenosine- and cold-stimulated MBF were similar in patients with and without metabolic syndrome, whereas baseline MBF showed a stepwise increase with increasing features of the syndrome. Consequently, patients with metabolic syndrome showed a lower coronary flow reserve (CFR) (2.5 ± 1.0) than those without metabolic syndrome (3.0 ± 0.9, P = 0.004). Differences in CFR were no longer present after correcting rest flows for the rate-pressure product. Change in MBF and CFR at 1 y were not different across groups of patients with increasing features of the metabolic syndrome.

CONCLUSION

Patients with metabolic syndrome demonstrate impaired CFR, which is related to the augmentation in resting coronary blood flow caused by hypertension. In high-risk individuals, peak adenosine- and cold-stimulated blood flows are impaired even in the absence of the metabolic syndrome.

We have observed in clinical practice that Native Americans require lower dosages of tacrolimus to attain similar target blood trough levels compared to whites after renal transplant. Because there are no pharmacokinetic studies of tacrolimus in this ethnic group, we investigated whether this clinical observation could be corroborated by pharmacokinetic differences between Native Americans and other ethnic and racial groups. We recruited 24 adult Native American kidney transplant recipients on stable oral doses of tacrolimus for at least 1 month posttransplant. We conducted a 12-h steady-state pharmacokinetic profile for all of the patients and estimated pharmacokinetic parameters using NONMEM. The concentration-time data were fit to a linear two compartment model with first-order absorption and lag time using an empirical Bayesian approach. The mean estimate of oral clearance (CL/F) was 11.1 l/h. Compared with previously reported data in other ethnic and racial groups, the Native American cohort has approximately one third the clearance of other groups. Our pharmacokinetic study reveals the clinically observed low dose of tacrolimus in Native American renal transplant patients is associated with a decreased oral tacrolimus clearance. There is scant information available on the genetic or environmental characteristics unique to this ethnic group that affect pharmacokinetics compared to other, better-studied groups, and elucidation of these factors will provide information to further facilitate individualized drug treatment for tacrolimus and a wide range of other drugs with similar clearance processes.

In the United States and globally, increasing numbers of older parents are living with their adult children. Making the decision to live together requires careful thought and planning; particularly when the decision means the children will be responsible for their elder parents' care, the physicians of all parties should be consulted. More than one-third of caregivers state that they seek advice from their physician or other clinician when information is needed about this transition. Using the case of a couple receiving care from their daughter in her own home, we review the prevalence and epidemiology of adult children caring for a parent in the adult child's home, important issues to consider, and a framework for clinicians to help guide their patients through this transition. We describe the physician's ongoing role in caring for and advising both the older parent and the adult children during common stages of multigenerational living: before the move and during coresidency and subsequent care transitions.