Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.     

Bipotential effects of estrogen on growth hormone synthesis and storage in vitro

Increased pulses of serum GH coincide with rising estrogens during the reproductive cycle, suggesting estrogen regulation. However, there is lack of agreement about estrogen's direct effects on the pituitary. Pituitaries from cycling female rats were dispersed and plated for 24 h in defined media containing vehicle or 0.001-250 nm 17beta-estradiol. Estrogen (0.01-10 nm) increased the percentages of GH antigen-bearing cells in the anterior pituitary significantly (1.3- to 1.6-fold) and 0.01-1 nm concentrations also stimulated significant increases in GH mRNA-bearing cells and in the integrated OD for GH mRNA. However, 100-250 nm either had no effect or, inhibitory effects on the area of label for GH mRNA. To test estrogen's effects on expression of GHRH receptors, cultures were stimulated with biotinylated analogs of GHRH and target cells detected by affinity cytochemistry. Estrogen increased GHRH target cells in populations from rats in all stages of the cycle tested. Basal expression of GHRH target cells declined at metestrus. Cultures treated with 0-1 nm estrogen were then dual labeled for bio-GHRH followed by immunolabeling for GH with the antirabbit IgG-ImmPRESS peroxidase polymer. Over 98% of GH cells bound GHRH and 90-96% of GHRH-bound cells contained GH in all treatment groups. Thus, low concentrations of estrogen may stimulate expression of more cells with GH proteins, biotinylated GHRH binding sites, and GH mRNA, whereas high concentrations have no effect, or may reduce GH mRNA. These bipotential effects may help explain the different findings reported in the literature.     

Identification of reptilian and amphibian blood meals from mosquitoes in an eastern equine encephalomyelitis virus focus in central Alabama

Uranotaenia sapphirina, Culex erraticus, and Cx. peccator were collected in an enzootic eastern equine encephalomyelitis (EEE) virus focus in central Alabama (Tuskegee National Forest) from 2001 to 2003 and analyzed for virus as well as host selection. EEE virus was detected in each species every year except 2003, when pools of Cx. peccator were negative. Most (97%) of the 130 Cx. peccator blood meals identified were from ectothermic hosts; 3% were from birds. Among blood meals from reptiles (approximately 75% of the total), 81% were from Agkistrodon piscivorus (cottonmouth); all amphibian blood meals (approximately 25%) were from Rana spp. with > 50% taken from the bullfrog R. catesbeiana. Host identifications were made from 131 of 197 Cx. erraticus, but only 3 (2%) were derived from ectothermic species. Identification of Ur. sapphirina blood meals proved difficult and only 2 of 35 hosts were determined. Both were from R. catesbeiana. Ectothermic species are possible EEE virus reservoirs in the southeastern United States where species such as Cx. peccator and Ur. sapphirina occur with large, diverse reptilian, amphibian, and avian populations such as those at the Tuskegee site.     

Physician Burnout and Patient-Physician Communication During Primary Care Encounters

Background  Although previous studies suggest an association between provider burnout and suboptimal self-reported communication, no studies relate physician burnout to observed patient-physician communication behaviors. Objective  To investigate the relationship between physician burnout and observed patient-physician communication outcomes in patient-physician encounters. Design  Longitudinal study of enrollment data from a trial of interventions to improve patient adherence to hypertension treatment. Setting  Fifteen urban community-based clinics in Baltimore, MD. Participants  Forty physicians and 235 of their adult hypertensive patients, with oversampling of ethnic minorities and poor persons. Fifty-three percent of physicians were women, and the average practice experience was 11.2 years. Among the 235 patients, 66% were women, 60% were African-American, and 90% were insured. Measurements  Audiotape analysis of communication during outpatient encounters (one per patient) using the Roter Interaction Analysis System and patients’ ratings of satisfaction with and trust and confidence in the physician. Results  The median time between the physician burnout assessment and the patient encounter was 15.1 months (range 5.6–30). Multivariate analyses revealed no significant differences in physician communication based on physician burnout. However, compared with patients of low-burnout physicians, patients of high-burnout physicians gave twice as many negative rapport-building statements (incident risk ratio 2.06, 95% CI 1.58 – 2.86, p < 0.001). Physician burnout was not significantly associated with physician or patient affect, patient-centeredness, verbal dominance, or length of the encounter. Physician burnout was also not significantly associated with patients’ ratings of their satisfaction, confidence, or trust. Conclusions  Physician burnout was not associated with physician communication behaviors nor with most measures of patient-centered communication. However, patients engaged in more rapport-building behaviors. These findings suggest a complex relationship between physician burnout and patient-physician communication, which should be investigated and linked to patient outcomes in future research.     

Risk of progression to AIDS and death in women infected with HIV-1 initiating highly active antiretroviral treatment at different stages of disease

BACKGROUND: The optimal virologic and immunologic stage at which to initiate antiretroviral therapy in individuals infected with human immunodeficiency virus type 1 (HIV-1) is undefined. METHODS: Among 1054 HIV-1-infected women in a prospective cohort study, we determined the time from initiation of highly active antiretroviral treatment (HAART) to acquired immunodeficiency syndrome (AIDS) and death. RESULTS: Median follow-up was 3.4 years. Of 553 women without AIDS at HAART initiation, 62 (11%) developed AIDS. Compared with women with CD4(+) cell counts greater than 350/microL at HAART initiation, women with cell counts of 200 to 350/microL and less than 200/microL had relative hazards (RHs) for progression to AIDS of 0.93 (95% confidence interval [CI], 0.46-1.86) and 2.48 (95% CI, 1.39-4.42), respectively. Compared with those with HIV-1 RNA values less than 5000 copies/mL, women with 5000 to 50,000 copies/mL and greater than 50,000 copies/mL had RHs of 1.39 (95% CI, 0.74-2.64) and 2.09 (95% CI, 1.09-3.99), respectively. Among women with AIDS at HAART initiation (n = 501), RHs of death were 1.97 (95% CI, 0.84-4.66) and 3.35 (95% CI, 1.59-7.08) with CD4(+) cell counts of 200 to 350/microL and less than 200/microL, respectively, relative to those with greater than 350/microL, and 1.90 (95% CI, 0.84-4.30) and 3.70 (95% CI, 1.81-7.54) for those with HIV-1 RNA values of 5000 to 50,000 and greater than 50,000 copies/mL, respectively, relative to those with less than 5000 copies/mL. CONCLUSIONS: Progression to AIDS and death was predicted by pre-HAART values of less than 200/microL for CD4(+) cells and greater than 50,000 HIV-1 RNA copies/mL, indicating that deferral of HAART until the CD4(+) cell count is between 350 and 200/microL is a valid strategy in the clinical management of HIV-1 infection.     

Effects of Deviant Child Behavior on Parental Alcohol Consumption: Stress-Induced Drinking in Parents of ADHD Children

Distress and ad lib alcohol consumption after interactions with child confederates were investigated in parents of children with externalizing disorders—attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD), or oppositional defiant disorder (ODD). Sixty subjects interacted with boys trained to act like either normal children or children with ADHD/CD/ODD. Interactions with deviant confederates resulted in feelings of inadequacy and produced negative affect but had no effect on alcohol consumption. Post hoc analyses showed that parents with a family history of alcohol problems (FH+) showed increased drinking after interaction with a deviant confederate, compared with FH+ parents who interacted with the normal confederate. FH- parents showed the opposite pattern of results. (Am J Addict 1998; 7:103–114)