Should We Treat Acute HIV Infection?

Critical advances in the early diagnosis of HIV now allow for treatment opportunities during acute infection. It remains unclear whether treatment of acute HIV infection with antiretroviral therapy improves long-term clinical outcomes for the individual and current guidelines are not definitive in recommending therapy at this stage of infection. However, treatment of acute HIV infection may have short-term benefit on viral set point when compared to delayed therapy as well as reducing the risk of transmission to others. Herein we review the immunological and clinical literature to discuss whether we should treat acute HIV infection, both from the perspective of the individual HIV-infected patient and from the public health perspective. As transmission of drug-resistant HIV variants are of concern, we also review recent clinical trial data to provide recommendations for which specific antiretroviral treatment regimens should be considered for the treatment of acute HIV infection.     

Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2-8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms.     

Interpersonal psychotherapy versus brief supportive therapy for depressed infertile women: first pilot randomized controlled trial

Infertility is strongly associated with depression, yet treatment research for depressed infertile women is sparse. This study tested for the first time the feasibility and preliminary efficacy of interpersonal psychotherapy (IPT), the evidence-based antidepressant intervention with the greatest peripartum research support, as treatment for depressed women facing fertility problems. Patients who met DSM-IV criteria for major depressive disorder of at least moderate severity were randomized to either 12 sessions of IPT (n?=?15) or brief supportive psychotherapy (BSP; n?=?16), our control intervention. Eighty percent of IPT and 63 % of BSP patients completed the 12 sessions of therapy. Patients in both treatments improved. IPT produced a greater response rate than BSP, with more than two-thirds of women achieving a >50 % reduction in scores on the Montgomery-?sberg Depression Rating Scale (MADRS). IPT also tended to have lower posttreatment scores on the Beck Depression Inventory, Clinical Global Impression-Severity Scale, and anxiety subscale of the Hamilton Depression Rating Scale, with between-group effect sizes ranging from 0.61 to 0.76. Gains persisted at 6-month follow-up. This pilot trial suggests that IPT is a promising treatment for depression in the context of infertility and that it may fare better than a rigorous active control condition. Should subsequent randomized controlled trials support these findings, this will inform clinical practice and take an important step in assuring optimal care for depressed women struggling with infertility.     

Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents

Aggregatibacter actinomycetemcomitans is frequently associated with localized aggressive periodontitis (LAP); however, longitudinal cohort studies relating A. actinomycetemcomitans to initiation of LAP have not been reported. A periodontal assessment was performed on 1,075 primarily African-American and Hispanic schoolchildren, ages 11 to 17 years. Samples were taken from each child for A. actinomycetemcomitans. A cohort of 96 students was established that included a test group of 38 A. actinomycetemcomitans-positive students (36 periodontally healthy and 2 with periodontal pockets) and 58 healthy A. actinomycetemcomitans-negative controls. All clinical and microbiological procedures were repeated at 6-month intervals. Bitewing radiographs were taken annually for definitive diagnosis of LAP. At the initial examination, clinical probing attachment measurements indicated that 1.2% of students had LAP, while 13.7% carried A. actinomycetemcomitans, including 16.7% of African-American and 11% of Hispanic students (P = 0.001, chi-square test). A. actinomycetemcomitans serotypes a, b, and c were equally distributed among African-Americans; Hispanic students harbored predominantly serotype c (P = 0.05, chi-square test). In the longitudinal phase, survival analysis was performed to determine whether A. actinomycetemcomitans-positive as compared to A. actinomycetemcomitans-negative students remained healthy ("survived") or progressed to disease with attachment loss of >2 mm or bone loss (failed to "survive"). Students without A. actinomycetemcomitans at baseline had a significantly greater chance to remain healthy (survive) compared to the A. actinomycetemcomitans-positive test group (P = 0.0001). Eight of 38 A. actinomycetemcomitans-positive and none of 58 A. actinomycetemcomitans-negative students showed bone loss (P = 0.01). A. actinomycetemcomitans serotype did not appear to influence survival. These findings suggest that detection of A. actinomycetemcomitans in periodontally healthy children can serve as a risk marker for initiation of LAP.     

Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation

The cellular abundance of the cyclin-dependent kinase (Cdk) inhibitor p27 is regulated by the ubiquitin-proteasome system. Activation of p27 degradation is seen in proliferating cells and in many types of aggressive human carcinomas. p27 can be phosphorylated on threonine 187 by Cdks, and cyclin E/Cdk2 overexpression can stimulate the degradation of wild-type p27, but not of a threonine 187-to-alanine p27 mutant [p27(T187A)]. However, whether threonine 187 phosphorylation stimulates p27 degradation through the ubiquitin-proteasome system or an alternative pathway is still not known. Here, we demonstrate that p27 ubiquitination (as assayed in vivo and in an in vitro reconstituted system) is cell-cycle regulated and that Cdk activity is required for the in vitro ubiquitination of p27. Furthermore, ubiquitination of wild-type p27, but not of p27(T187A), can occur in G1-enriched extracts only upon addition of cyclin E/Cdk2 or cyclin A/Cdk2. Using a phosphothreonine 187 site-specific antibody for p27, we show that threonine 187 phosphorylation of p27 is also cell-cycle dependent, being present in proliferating cells but undetectable in G1 cells. Finally, we show that in addition to threonine 187 phosphorylation, efficient p27 ubiquitination requires formation of a trimeric complex with the cyclin and Cdk subunits. In fact, cyclin B/Cdk1 which can phosphorylate p27 efficiently, but cannot form a stable complex with it, is unable to stimulate p27 ubiquitination by G1 extracts. Furthermore, another p27 mutant [p27(CK-)] that can be phosphorylated by cyclin E/Cdk2 but cannot bind this kinase complex, is refractory to ubiquitination. Thus throughout the cell cycle, both phosphorylation and trimeric complex formation act as signals for the ubiquitination of a Cdk inhibitor.     

Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3: CPCRA 059

The effect of intermittent courses of recombinant interleukin-2 (rIL-2) on HIV-1 load in patients receiving combination antiretroviral therapy remains uncertain. CPCRA 059 was an open-label, randomized, multicenter trial in which 511 patients with HIV-1 infection and CD4+ cell counts of > or = 300/mm3 who were receiving antiretroviral therapy were assigned to receive no rIL-2 (255 patients [controls]) or subcutaneous rIL-2 in dosages of 4.5 MIU (130) or 7.5 MIU (126) twice daily for 5-day courses every 8 weeks to maintain CD4+ cell counts that were twice the baseline value or > or = 1,000/mm3. The primary objective of this study was to compare the effects of the two doses of rIL-2 and no rIL-2 on viral load and CD4+ cell counts over 12 months. There was no difference in the following viral load measurements between the rIL-2 treatment groups and the control treatment group: percentage of patients with viral loads of <50 copies/mL at 12 months (p =.55), time to viral load of > or = 50 copies/mL for patients who had baseline viral loads of <50 copies/mL (p =.35), and change in viral load from baseline for patients who had viral loads of > or = 50 copies/mL at baseline (p =.63). At each follow-up visit, the change in CD4+ cell count from baseline was significantly greater in the rIL-2 treatment groups than in the control treatment group, with a mean difference of 251/mm3 at month 12 (95% confidence interval, 207-295; p <.0001). No unanticipated adverse experiences were seen in this trial, to our knowledge the largest randomized evaluation of rIL-2 treatment conducted to date.     

Psychological Response of Firefighters to a Chemical Fire

Abstract

Samples of firefighter subjects (n = 80) and a comparison group (n = 15) were contrasted on a number of postincident psychological distress measures in the aftermath of a polyvinyl chloride (PVC) fire. Using a structured, self-administered questionnaire, firefighter subjects were found to be more psychologically distressed on demoralization, specific emotional distress, and perceived threat to physical health. After controlling for baseline characteristics on which subjects and the comparison group differed, these between-group effects remained significant. The three outcome scales, while correlated, measure different components of psychological distress.