Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy

OBJECTIVES We sought to determine if a hypertensive response to exercise (HRE) is associated with myocardial changes consistent with early hypertensive heart disease. BACKGROUND An HRE predicts the development of chronic hypertension (HT) and may reflect a preclinical stage of HT. METHODS Patients with a normal left ventricular (LV) ejection fraction and a negative stress test were recruited into three matched groups: 41 patients (age 56 +/- 10 years) with HRE (210/105 mm Hg in men; > 190/105 in women), comprising 22 patients with (HT+) and 19 without resting hypertension (HT-); and 17 matched control subjects without HRE. Long-axis function was determined by measurement of the strain rate (SR), peak systolic strain, and cyclic variation (CV) of integrated backscatter in three apical views. RESULTS An HRE was not associated with significant differences in LV mass index. Exercise performance and diastolic function were reduced in HRE(HT+) patients, but similar in HRE(HT-) patients and controls. Systolic dysfunction (peak systolic strain, SR, and CV) was significantly reduced in HRE patients (p < 0.001 for all). These reductions were equally apparent in patients with and without a history of resting HT (p = NS) and were independent of LV mass index and blood pressure (p < 0.01). CONCLUSIONS An HRE is associated with subtle systolic dysfunction, even in the absence of resting HT. These changes occur before the development of LV hypertrophy or detectable diastolic dysfunction and likely represent early hypertensive heart disease. (C) 2004 by the American College of Cardiology Foundation.

Impaired Antigen Presentation and Effectiveness of Combined Active/Passive Immunotherapy for Epithelial Tumors

Background: Although immunization with tumor antigens can eliminate many transplantable tumors in animal models, immune effector mechanisms associated with successful immunotherapy of epithelial cancers remain undefined. Methods: Skin from transgenic mice expressing the cervical cancer-associated tumor antigen human papillornavirus type 16 (HPV16) E6 or E7 proteins from a keratin 14 promoter was grafted onto syngeneic, non-transgenic mice. Skin graft rejection was measured after active immunization with HPV16 E7 and adoptive transfer of antigen-specific T cells. Cytokine secretion of lymphocytes from mice receiving skin grafts and immunotherapy was detected by enzyme-linked immunosorbent assay, and HPV16 E7-specific memory CD8(+) T cells were detected by flow cytometry and ELISPOT. Results: Skin grafts containing HPV16 E6- or E7-expressing keratinocytes were not rejected spontaneously or following immunization with E7 protein and adjuvant. Adoptive transfer of E7-specific T-cell receptor transgenic CD8(+) T cells combined with immunization resulted in induction of antigen-specific interferon gamma-secreting CD8(+) T cells and rejection of HPV16 E7-expressing grafts. Specific memory CD8(+) T cells were generated by immunotherapy. However, a further HPV16 E7 graft was rejected from animals with memory T cells only after a second E7 immunization. Conclusions: Antigen-specific CD8(+) T cells can destroy epithelium expressing HPV16 E7 tumor antigen, but presentation of E7 antigen from skin is insufficient to reactivate memory CD8(+) T cells induced by immunotherapy. Thus, effective cancer immunotherapy in humans may need to invoke sufficient effector as well as memory T cells.

Desire to drink in low- and high-risk social drinkers: An experimental analogue of impaired control

This study used a novel cue exposure paradigm to investigate the differences between high- and low-risk drinkers in their desire to drink during a drinking session. Fifty-three self-selected participants were assigned to high- or low-risk drinking groups based on their self-reported consumption of alcohol, then compared on their desire to drink over a 90 min paced drinking session. High-risk drinkers showed increasing desire over the session, while low-risk drinkers' desire began to decrease after only a short drinking period. The perceived and actual effects of the alcohol did not appear to be able to account for the difference. Results are discussed with reference to issues of impaired control. Suggestions for future research directions are also offered.

Parasitization of Manduca sexta larvae by the parasitoid wasp Cotesia congregata induces an impaired host immune response

During oviposition, the parasitoid wasp Cotesia congregata injects polydnavirus, venom, and parasitoid eggs into larvae of its lepidopteran host.. the tobacco hornworm, Manduca sexta. Polydnaviruses (PDVs) suppress the immune system of the host and allow the juvenile parasitoids to develop without being encapsulated by host hemocytes mobilized by the immune system. Previous work identified a gene in the Cotesia rubecula PDV (CrV1) that is responsible for depolymerization of actin in hemocytes of the host Pieris rapae during a narrow temporal window from 4 to 8 h post-parasitization. Its expression appears temporally correlated with hemocyte dysfunction. After this time, the hemocytes recover, and encapsulation is then inhibited by other mechanism(s). In contrast, in parasitized tobacco hornworm larvae this type of inactivation in hemocytes of parasitized M. sexta larvae leads to irreversible cellular disruption. We have characterized the temporal pattern of expression of the CrV1-homolog from the C. congregata PDV in host fat body and hemocytes using Northern blots, and localized the protein in host hemocytes with polyclonal antibodies to CrV1 protein produced in P. rapae in response to expression of the CrV1 protein. Host hemocytes stained with FITC-labeled phalloidin, which binds to filamentous actin, were used to observe hemocyte disruption in parasitized and virus-injected hosts and a comparison was made to hemocytes of nonparasitized control larvae. At 24 h post-parasitization host hemocytes were significantly altered compared to those of nonparasitized larvae. Hemocytes front newly parasitized hosts displayed blebbing, inhibition of spreading and adhesion, and overall cell disruption. A CrV1-homolog gene product was localized in host hemocytes using polyclonal CrV1 antibodies, suggesting that CrV1-like gene products of C. congregata's bracovirus are responsible for the impaired immune response of the host. (C) 2005 Elsevier Ltd. All rights reserved.

Impaired memory and olfactory performance in NaSi-1 sulphate transporter deficient mice

In the present study, NaSi-l sulphate transporter knock-out (Nas1-/-) mice, an animal model of hyposulphataernia, were examined for spatial memory and learning in a Morris water maze, and for olfactory function in a cookie test. The Nas1-/- mice displayed significantly (P < 0.05) increased latencies to find an escape platform in the reversal teaming trials at 2 days but not 1 day after the last acquisition trial in a Morris water maze test. suggesting that Nas1-/- mice may have proactive memory interference. While the wild-type (Ncis1+/+) mice showed a significant (P < 0.02) decrease in time to locate a hidden food reward over four trials after overnight fasting, Nas1-/- mice did not change their performance, resulting in significantly (P < 0.05) higher latencies when compared to their Nas1+/+ littermates. There were no significant differences between Nas1-/- and Nas1+/+ mice in the cookie test after moderate food deprivation. In addition, both Nas1-/- and Nas1+/+ mice displayed similar escape latencies in the acquisition phase of the Morris water maze test, suggesting that learning, motivation, vision and motor skills required for the task may not be affected in Nas1-/- mice. This is the first study to demonstrate an impairment in memory and olfactory performance in the hyposulphataemic Nas1-/- mouse. (c) 2004 Elsevier B.V. All rights reserved.

Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis

The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCV-infected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r = 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r = 0.544, P < .0001) and the ductular area (r = 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r = 0.372, P = .0004) and ductular reaction (r = 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P = .002) and increased with the body mass index (P < .001) and lobular inflammation (P = .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases.

Renal endothelial dysfunction and impaired autoregulation after ischemia-reperfusion injury result from excess nitric oxide

Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase ( eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide ( NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral ( U) or bilateral ( B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC50 was increased, and endothelium-derived hyperpolarizing factor ( EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance ( RVR) in B60 kidneys; this facilitated autoregulation, and the increase in RVR was abolished by 100 mu M furosemide. Autoregulation was enhanced by N-omega-nitro-L-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.

Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia

Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice (Vegfb(-/-)). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile. Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis. The full text of this article is available at http://www.circresaha.org.