Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia

Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional manifestations associated with the intermediate phenotype and the clinical illness. Neuroimaging of preclinical neurodevelopmental approaches such as methylazoxymethanol acetate (MAM) exposure may afford a powerful translational tool to establish endpoints with greater congruency across animals and humans. Using in vivo volumetric magnetic resonance imaging (MRI), manganese‐enhanced MRI, and diffusion tensor imaging (DTI), we investigated morphological and cytoarchitectural changes of brain structures in MAM‐exposed rats, a neurodevelopmental model of schizophrenia. Compared to saline‐exposed controls, MAM‐exposed rats showed significant enlargement of lateral and third ventricles as well as reduced hippocampal volumes, which is consistent with findings observed in schizophrenia. In addition, DTI revealed that diffusion fractional anisotropy retrieved from corpus callosum and cingulum were significantly decreased in MAM‐exposed rats, suggesting that demyelination occurred in these white‐matter fiber tracts. Imaging findings were confirmed by conducting histological analysis using hematoxylin and eosin and Luxol fast blue stainings. In summary, structural abnormalities resulting from a MAM environmental challenge parallel cerebral pathology observed in schizophrenia. The MAM model incorporating noninvasive imaging techniques may therefore serve as an improved translational research tool for assessing new treatments for schizophrenia. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Acquisition of anal human papillomavirus (HPV) infection in women: the Hawaii HPV Cohort study

BACKGROUND: The majority of anal cancer is associated with human papillomavirus (HPV) infection, yet little is known about women's risk of acquisition of anal HPV infection. METHODS: Risk factors for the acquisition of anal HPV infection were examined in a longitudinal cohort study of 431 women, via repeated measurement of HPV DNA. RESULTS: Seventy percent of women were positive for anal HPV infection at one or more clinic visits from baseline through a follow-up period that averaged 1.3 years. The incidence of a high-risk (HR) infection was 19.5 (95% confidence interval [CI], 16.0-23.6) per 1000 woman-months. The most common incident HR HPV types were HPV-53, -52 and -16. The presence of an HR anal HPV infection at baseline increased the risk of an incident anal infection by 65%. Baseline HR cervical HPV infection also predicted the acquisition of an HR anal HPV infection (odds ratio, 1.81 [95% CI, 1.09-3.02]). Nonviral risk factors for acquisition of HR HPV infection included younger age, lower socioeconomic status, greater lifetime number of sexual partners, past use of hormones, and condom use. CONCLUSIONS: The results of this study suggest that women's risk of anal HPV infection is as common as their risk of cervical HPV infection.     

Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure

OBJECTIVES: The goal of this study was to determine the prevalence of worsening renal function (WRF) among hospitalized heart failure (HF) patients, clinical predictors of WRF, and hospital outcomes associated with WRF. BACKGROUND: Impaired renal function is associated with poor outcomes among chronic HF patients. METHODS: Chart reviews were performed on 1,004 consecutive patients admitted for a primary diagnosis of HF from 11 geographically diverse hospitals. Cox regression model analysis was used to identify independent predictors for WRF, defined as a rise in serum creatinine of >0.3 mg/dl (26.5 micromol/l). Bivariate analysis was used to determine associations of development of WRF with outcomes (in-hospital death, in-hospital complications, and length of stay). RESULTS: Among 1,004 HF patients studied, WRF developed in 27%. In the majority of cases, WRF occurred within three days of admission. History of HF or diabetes mellitus, admission creatinine > or =1.5 mg/dl (132.6 micromol/l), and systolic blood pressure >160 mm Hg were independently associated with higher risk of WRF. A point score based on these characteristics and their relative risk ratios predicted those at risk for WRF. Hospital deaths (adjusted risk ratio [ARR] 7.5; 95% confidence intervals [CI] 2.9, 19.3), complications (ARR 2.1; CI 1.5, 3.0), and length of hospitalizations >10 days (ARR 3.2, CI 2.2, 4.9) were greater among patients with WRF. CONCLUSIONS: Worsening renal function occurs frequently among hospitalized HF patients and is associated with significantly worse outcomes. Clinical characteristics available at hospital admission can be used to identify patients at increased risk for developing WRF.     

Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.     

Sympathetic nervous system function as measured by I-123 metaiodobenzylguanidine predicts transplant-free survival in heart failure patients with idiopathic dilated cardiomyopathy

BACKGROUND: Heightened activity of the sympathetic nervous system in heart failure patients is a major contributor to disease progression and death. I-123 metaiodobenzylguanidine (MIBG) provides an accurate, noninvasive method to assess cardiac sympathetic nerve activity. METHODS: Thirty-seven patients with New York Heart Association class II, III, or IV heart failure underwent baseline measurement of I-123 MIBG heart-to-mediastinum ratios, maximum oxygen consumption, radionuclide left ventricular ejection fraction, and plasma norepinephrine levels. Patients were followed 48.8+/-8.6 months to endpoints of cardiac death or transplantation. The heart-to-mediastinum ratio of I-123 MIBG activity measured 15 minutes after injection was the only independent predictor of transplant-free survival (P<.0001). I-123 MIBG imaging at 15 minutes identified patients with subsequent cardiac transplantation or death with a sensitivity of 92% and specificity of 72%, whereas the corresponding values for maximum oxygen consumption were 75% and 56%. By Kaplan-Meier survival analysis, the time to a cardiac endpoint was significantly shorter in patients with a 15-minute I-123 MIBG heart-to-mediastinum ratio below the group mean ratio of 1.536, compared with patients with a preserved I-123 MIBG ratio. Maximum oxygen consumption was not predictive of time to cardiac transplant or death. CONCLUSIONS: In this study of patients with congestive heart failure resulting from dilated cardiomyopathy, a 15-minute heart-to-mediastinum ratio of I-123 MIBG activity provided more accurate prediction of cardiac transplantation or death than other standard clinical tests.     

Managing abnormal blood lipids: a collaborative approach

Current data and guidelines recommend treating abnormal blood lipids (ABL) to goal. This is a complex process and requires involvement from various healthcare professionals with a wide range of expertise. The model of a multidisciplinary case management approach for patients with ABL is well documented and described. This collaborative approach encompasses primary and secondary prevention across the lifespan, incorporates nutritional and exercise management as a significant component, defines the importance and indications for pharmacological therapy, and emphasizes the importance of adherence. Use of this collaborative approach for the treatment of ABL ultimately will improve cardiovascular and cerebrovascular morbidity and mortality.     

Adiposity is related to gender differences in impaired stress-induced pressure natriuresis

The purpose of this study was to determine if there are gender differences in stress-induced pressure natriuresis and to examine the effects of adiposity on these differences. The subjects were 151 boys and 141 girls 15 to 18 years of age who underwent a 5-hour stress protocol (2-hour prestress, 1-hour stress, 2-hour poststress) after being brought into similar levels of sodium balance. The gender-by-condition interaction was significant for systolic and diastolic blood pressure (P=0.001 for both), and the effect of condition was significant for sodium excretion (P=0.001). Systolic blood pressure was higher for boys throughout the protocol (P=0.001 for each) and correlated with body mass index at each condition (range in r=0.28 to 0.35; P<0.001 for each). Hemodynamically, in boys body mass index was correlated with cardiac output during stress (r=0.23; P=0.006), which was correlated with systolic blood pressure (r=0.21; P=0.01). With respect to natriuresis, body mass index was inversely correlated with sodium excretion during stress (r=-0.22; P=0.008) and positively correlated with angiotensin II in a subsample of boys (n=89: r=0.31; P=0.003). The inverse correlation between angiotensin II and sodium excretion during stress approached significance (r=-0.17; P<0.06). Similar results were not observed for girls. In conclusion, gender differences in stress-induced pressure natriuresis appear to be related to the influence of adiposity on both blood pressure and natriuresis.