Systemic activation of integrin alphaVbeta3 in donors with spontaneous intracerebral hemorrhage is associated with subsequent development of vasculopathy in the heart transplant recipient.

BACKGROUND: Recipients of hearts from donors with spontaneous intracerebral hemorrhage (ICH) are at increased risk of allograft vasculopathy compared with trauma donors. We have recently shown that the vitronectin receptor (integrin alpha(V)beta3) is upregulated in transplant vasculopathy. We hypothesized that donor ICH is associated with systemic activation of alpha(V)beta3 in the donor before transplantation. METHODS: We evaluated mRNA expressions of alpha(V)beta3 (TaqMan PCR) in endomyocardial biopsy samples at 1-week post-transplant in 20 recipients from ICH donors and 20 recipients from trauma donors. To investigate whether systemic activation of alpha(V)beta3 was present in the donor before transplantation, alpha(V)beta3 expression was also evaluated in the corresponding donor spleen lymphocytes. All patients underwent serial coronary intravascular ultrasound to evaluate for coronary vasculopathy. The baseline characteristics were similar except for increased donor age in the ICH Group. RESULTS: The ICH Group showed significant increased mRNA expression of alpha(V)beta3 in the heart biopsy samples (3.8-fold, p = 0.012) and in the corresponding donor spleen lymphocytes (3.5-fold, p = 0.014) compared with the Trauma Group. At 1 year, the ICH Group also showed increased progression of coronary vasculopathy. Multivariate regression analysis found that donor lymphocytic alpha(V)beta3 mRNA expression was independently associated with increased risk of vasculopathy (odds ratio, 1.9; 95% CI, 1.21-3.98, p = 0.03). CONCLUSIONS: Our report demonstrates the presence of systemic activation of alpha(V)beta3 in donors with spontaneous intracerebral hemorrhage and its association with the subsequent development of allograft vasculopathy in the recipient.     

Patients' Expectations of Asthma Treatment

A multicomponent model has been developed to explain patients' unmet expectations of medical care. The model proposes that expectations are related to patients' personal experiences with illness, perceived vulnerability to disease, transmitted knowledge, and perceived severity of disease. The objective of this cross-sectional study was to determine whether this model can be applied to patients' unrealistic expectations of treatment outcomes, specifically expecting to be cured of asthma. In total, 230 patients observed in a primary care practice in New York City were interviewed in person with open-ended questions about their expectations of asthma treatment. Responses were analyzed with qualitative techniques to generate categories of expectations. Patients had a mean age of 41 ± 11 years, 21% were white, 30% African American, 42% Latino, and 7% other groups. Major categories of expectations were generated from patients' responses and included symptom relief (expected by 52%), cure (36%), improved physical function (21%), and improved psychological well-being (15%). The category of expecting a cure was assessed with patients' responses to the following items representing components of the model: 1) resource utilization and medication requirements for asthma (representing severity of disease); 2) perceived quality of asthma care and satisfaction with care (representing past asthma experiences); 3) the Asthma Self-Efficacy Scale (representing perceived vulnerability to exacerbations); and 4) experiences of social network contacts with asthma and the Check Your Asthma IQ survey (representing transmitted knowledge). In bivariate analysis, patients who expected a cure were more likely to be Latino or Native American or Asian (p = 0.02), to have never required oral corticosteroids (p = 0.004), to be dissatisfied with the status of their asthma (p = 0.008), to know others who were limited by asthma (p = 0.03), to have worse Asthma Self-Efficacy Scale scores (p = 0.002), to have worse Check Your Asthma IQ scores (p = 0.04), and to currently be taking inhaled corticosteroids (p = 0.03). In multivariate analysis, worse asthma self-efficacy (p = 0.008), never having required oral corticosteroids (p = 0.005), and currently taking inhaled corticosteroids (p = 0.05) remained associated with expecting a cure. As a result of this study, we found that patients have multiple expectations of asthma treatment, including realistic expectations such as symptom relief and improved function, as well as unrealistic expectations, specifically to be cured of asthma. A multicomponent model of patient and disease characteristics was associated with this unrealistic expectation. These findings indicate that clinicians can intervene in diverse areas to foster realistic expectations of treatment outcomes among asthma patients.     

The effect of combined Angiotensin-converting enzyme inhibition and calcium antagonism on allograft coronary vasculopathy validated by intravascular ultrasound.

BACKGROUND: Hypertension is a potential risk factor for allograft coronary vasculopathy. We evaluated the efficacy of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, and their combined use, on the development of coronary vasculopathy in hypertensive heart transplant recipients. METHODS: Eighty-two heart transplant recipients underwent serial intravascular ultrasound (IVUS) analysis at baseline (within 1 month) and at 1 year after transplantation and were evaluated for the development of coronary vasculopathy. Patients were divided into 4 groups. Nineteen normotensive recipients received no treatment, control (Group A). Hypertensive patients were treated with either ACE inhibitors (Group B, n = 37), calcium antagonists (Group C, n = 16), or both (Group D, n = 10). RESULTS: We found a significant reduction in IVUS indices of coronary vasculopathy in heart transplant recipients who used a combination of an ACE inhibitor and a calcium antagonist compared with recipients who used either drug alone (p < 0.05). This synergistic efficacy was independent of the baseline indices evaluated in a multivariate regression analysis model and was noted despite comparable mean arterial pressure among the 3 hypertensive groups at 1 year, thus suggesting the presence of a synergistic anti-proliferative effect beyond the anti-hypertensive efficacy. CONCLUSIONS: The combined use of an ACE inhibitor and a calcium antagonist is more effective than the individual use of either drug alone on the development of coronary vasculopathy in cardiac transplant recipients. Large randomized clinical trials are warranted to evaluate such a synergistic efficacy.     

Burkholderia thailandensis Isolated from the Environment,United States

Burkholderia thailandensis, an opportunistic pathogen found in the environment, is a bacterium closely related to B. pseudomallei, the cause of melioidosis. Human B. thailandensis infections are uncommon. We isolated B. thailandensis from water in Texas and Puerto Rico and soil in Mississippi in the United States, demonstrating a potential public health risk.     

Acute inflammation induced by the biopsy of mouse mammary tumors promotes the development of metastasis

Development of metastasis in peripheral tissues is a major problem in the fight to cure breast cancer. Although it is becoming evident that chronic inflammation can contribute to tumor progression and metastasis, the effect of acute inflammation in primary tumor is less known. Using mouse models for breast cancer here we show that biopsy of mammary tumors increases the frequency of lung metastases. This effect is associated with the recruitment of inflammatory cells to the lung and elevated levels of certain cytokines such as IL-6 in the lung airways. Antiinflammatory treatment prior to and after the biopsy reduces the development of metastases triggered by the biopsy. In addition, while lack of IL-6 does not affect primary tumor development, it protects from increasing number of metastases upon biopsy. Thus, our studies show that in addition to chronic inflammation, acute immune response caused by invasive procedures in the primary tumor may cause an increased risk on peripheral metastases, but the risk could be decreased by anti-inflammatory treatments.     

Genetic Variants Influencing Joint Damage in Mexican Americans and European Americans With Rheumatoid Arthritis

Joint destruction in rheumatoid arthritis (RA) is heritable, but knowledge on specific genetic determinants of joint damage in RA is limited. We have used the Immunochip array to examine whether genetic variants influence variation in joint damage in a cohort of Mexican Americans (MA) and European Americans (EA) with RA. We studied 720 MA and 424 EA patients with RA. Joint damage was quantified using a radiograph of both hands and wrists, scored using Sharp's technique. We conducted association analyses with the transformed Sharp score and the Immunochip single nucleotide polymorphism (SNP) data using PLINK. In MAs, 15 SNPs from chromosomes 1, 5, 9, 17 and 22 associated with joint damage yielded strong p‐values (p < 1 × 10^?4). The strongest association with joint damage was observed with rs7216796, an intronic SNP located in the MAP3K14 gene, on chromosome 17 (β ± SE = ?0.25 ± 0.05, p = 6.23 × 10^?6). In EAs, 28 SNPs from chromosomes 1, 4, 6, 9, and 21 showed associations with joint damage (p‐value < 1 × 10^?4). The best association was observed on chromosome 9 with rs59902911 (β ± SE = 0.86 ± 0.17, p = 1.01 × 10^?6), a synonymous SNP within the CARD9 gene. We also observed suggestive evidence for some loci influencing joint damage in MAs and EAs. We identified two novel independent loci (MAP3K14 and CARD9) strongly associated with joint damage in MAs and EAs and a few shared loci showing suggestive evidence for association.     

Tissue-specific regulation of growth hormone (GH) receptor and insulin-like growth factor-I gene expression in the pituitary and liver of GH-deficient (lit/lit) mice and transgenic mice that overexpress bovine GH (bGH) or a bGH antagonist

GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell surface receptor (GHR). Expression of GHR is tissue specific and a requirement for cellular responsiveness to GH. IGF-I is produced in multiple tissues and regulated in part by GH through GHR. In this study, we evaluated GHR and IGF-I mRNA expression in pituitary gland and compared the levels with those derived from liver of bovine GH transgenic, GH antagonist transgenic, lit/lit mice, and their respective controls using real-time RT-PCR. In liver, both GHR and IGF-I mRNA expressions were regulated in parallel with GH action in all three animal models, and there was a strong correlation between GHR and IGF-I mRNA levels. In the pituitary gland, increased expression of IGF-I mRNA in the pituitary of bovine GH transgenic mice was observed, whereas IGF-I expression in GH antagonist transgenic or lit/lit mice was similar to that observed in control animals. There were no differences of GHR mRNA levels in pituitary gland of any groups we examined. There was also no correlation between GHR and IGF-I mRNA levels in any group in the pituitary gland. In conclusion, we found that hepatic GHR and IGF-I mRNA levels were strongly correlated with each other in chronic GH excess or deficient state, and that regulation and correlation between local GHR and IGF-I mRNA levels induced by GH is different between liver and pituitary gland.     

Current treatment options for intracerebral hemorrhage

Intracerebral hemorrhage (ICH) remains the least treatable form of stroke. Despite ongoing attempts to find effective interventions based on the physiopathologic understanding of this disease, evidence-based medical therapies for ICH are limited to recommendations on blood pressure (BP) reduction, intracranial pressure monitoring, osmotherapy with adequate fluid resuscitation, fever and glycemic control, and seizure prophylaxis. Although the value of surgical treatment remains in doubt because of the negative results of the International Surgical Trial in Intracerebral Haemorrhage (STICH), a subgroup analysis of this study suggested better outcomes among patients with superficial hematomas who underwent surgical evacuation, supporting the ongoing STICH-II trial. Other approaches currently under study include ultra-early hemostatic therapy and BP reduction, thrombolytic therapy for intraventricular hemorrhage, and minimally invasive surgical approaches.