Modeling a safer smallpox vaccination regimen, for human immunodeficiency virus type 1-infected patients, in immunocompromised macaques

We have modeled smallpox vaccination with Dryvax (Wyeth) in rhesus macaques that had depletion of CD4(+) T cells induced by infection with simian immunodeficiency virus or simian/human immunodeficiency virus. Smallpox vaccination induced significantly larger skin lesions in immunocompromised macaques than in healthy macaques. Unexpectedly, "progressive vaccinia" was infrequent. Vaccination of immunocompromised macaques with the genetically-engineered, replication-deficient poxvirus NYVAC, before or after retrovirus infection, was safe and lessened the severity of Dryvax-induced skin lesions. Neutralizing antibodies to vaccinia were induced by NYVAC, even in macaques with severe CD4(+) T cell depletion, and their titers inversely correlated with the time to complete resolution of the skin lesions. Together, these results provide the proof of concept, in macaque models that mirror human immunodeficiency virus type 1 infection, that a prime-boost approach with a highly attenuated poxvirus followed by Dryvax increases the safety of smallpox vaccination, and they highlight the importance of neutralizing antibodies in protection against virulent poxvirus.     

Salt loading exacerbates diastolic dysfunction and cardiac remodeling in young female Ren2 rats

ObjectiveRecent data would suggest pre-menopausal insulin resistant women are more prone to diastolic dysfunction than men, yet it is unclear why. We and others have reported that transgenic (mRen2)27 (Ren2) rats overexpressing the murine renin transgene are insulin resistant due to oxidative stress in insulin sensitive tissues. As increased salt intake promotes inflammation and oxidative stress, we hypothesized that excess dietary salt would promote diastolic dysfunction in transgenic females under conditions of excess tissue Ang II and circulating aldosterone levels.Materials/methodsFor this purpose we evaluated cardiac function in young female Ren2 rats or age-matched Sprague–Dawley (SD) littermates exposed to a high (4%) salt or normal rat chow intake for three weeks.ResultsCompared to SD littermates, at 10 weeks of age, female Ren2 rats fed normal chow showed elevations in left ventricular (LV) systolic pressures, LV and cardiomyocyte hypertrophy, and displayed reductions in LV initial filling rate accompanied by increases in 3-nitrotyrosine content as a marker of oxidant stress. Following 3 weeks of a salt diet, female Ren2 rats exhibited no further changes in LV systolic pressure, insulin resistance, or markers of hypertrophy but exaggerated increases in type 1 collagen, 3-nitrotryosine content, and diastolic dysfunction. These findings occurred in parallel with ultrastructural findings of pericapillary fibrosis, increased LV remodeling, and mitochondrial biogenesis.ConclusionThese data suggest that a diet high in salt in hypertensive female Ren2 rats promotes greater oxidative stress, maladaptive LV remodeling, fibrosis, and associated diastolic dysfunction without further changes in LV systolic pressure or hypertrophy.     

Osmotic control of the release of prolactin and thyrotropin in euthyroid subjects and patients with pituitary tumors.

The effects of acute changes in serum osmolality on basal serum PRL and TSH levels and on responses of prolactin (PRL) and thyrotropin (TSH) to the thyrotropin-releasing hormone (TRH) analogue, N3im-methyl-TRH, were studied in ten euthyroid subjects and in three patients with PRL-secreting pituitary tumors. An oral water load of 20 ml/kg had no effect on basal serum PRL or TSH levels but did result in an increased PRL response to methyl-TRH in the ten euthyroid patients. Intravenous infusion of 5% sodium chloride in the ten euthyroid subjects significantly depressed basal serum PRL levels but had no effect on the PRL response to methyl-TRH. Infusion of hypertonic saline significantly decreased the TSH response to methyl-TRH. In the three patients with pituitary tumors, oral water loading and hypertonic saline infusion had no significant effect on the basal serum PRL and TSH or the PRL and TSH responses to methyl-TRH. The patients with pituitary tumors had a higher basal serum osmolality and a proportionately higher serum concentration of arginine vasopressin than the euthyroid patients. These data suggest that changes in osmolality in euthyroid patients may have a direct effect on the anterior pituitary's PRL and TSH response to a releasing factor.     

Pituitary response to LHRH in midtrimester pregnancy.

The effects of lutenizing hormone releasing hormone (LHRH) on serum luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), thyroid stimulating hormone (TSH), and growth hormone (GH) were studied in 10 women in the second trimester of pregnancy. Serum LH was measured using the LHbeta-RIA, with the anti-betaLH serum being preabsorbed with purified hCG. This assay was unaffected by hCG levels up to 500 IU/ml. Basal serum levels of LH was undetectable and basal FSH levels were low in these 10 women. No release of LH or FSH was observed after administration of 100 microgram of LHRH. However, there was a statistically significant rise in PRL from mean basal levels of 139.9 ng/ml to a mean peak level of 159.0 ng/ml at 30 minutes after LHRH administration. Both TSH and GH displayed small elevations at 15 minutes after LHRH administration; however, these elevations were not significant because of the wide range in responses. The results of this study indicate that gonadotropin release is inhibited during the second trimester of pregnancy. Finally, it appears that pregnancy is a condition in which LHRH administration results in a nonspecific release of several hormones.     

Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS)

ObjectiveTo examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.MethodsWomen screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n = 650).ResultsHigher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r = 0.21 and 0.19, respectively; P < 0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides = ?0.16, 0.11, and 0.11, respectively, P < 0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4–1.6], 1.5 [0.8–2.9], and 1.8 [1.0–3.4]; p for linear trend = 0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.ConclusionWhile hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.     

Treatment of hypertension in patients with diabetes

At least 17 million people in the United States have diabetes mellitus, and another 50 million have hypertension. These chronic diseases increasingly coexist in our aging population. Both diseases are important predisposing factors for the development of cardiovascular disease (CVD) and renal disease, and the coexistence of these risk factors is a very powerful promoter of CVD and renal disease. There is accumulating evidence that the rigorous treatment of hypertension and other risk factors such as dyslipidemia and hyperglycemia considerably lessens the burden of CVD and renal disease in patients with diabetes mellitus. There is considerable evidence that strategies addressing diet and exercise reduce the development of diabetes and are an important component of treatment in persons who have established diabetes. There are also considerable data suggesting that the treatment strategies that interrupt the renin-angiotensin system have special benefits in patients with diabetes and may prevent the development of clinical diabetes in hypertensive patients with impaired glucose tolerance. Data from a recent study indicate that the control of systolic blood pressure, using a diuretic agent as part of antihypertensive therapy, reduces the risk of stroke and other CVD end points. Recent reports indicate that angiotensin receptor-blocking agents decrease the rate of development of proteinuria and diabetic renal disease. These observations will likely have a significant impact on treatment of hypertension in patients with type 2 diabetes mellitus.     

Tumor interstitial fluid pressure may regulate angiogenic factors in osteosarcoma

We have previously shown that osteosarcomas (OS) have states of increased interstitial fluid pressure (IFP), which correlate with increased proliferation and chemosensitivity. In this study, we hypothesized that constitutively raised IFP in OS regulates angiogenesis. Sixteen patients with the clinical diagnosis of OS underwent blood flow and IFP readings by the wick‐in‐needle method at the time and location of open biopsy. Vascularity was determined by capillary density in the biopsy specimens. We performed digital image analysis of immunohistochemical staining for CD31, VEGF‐A, VEGF‐C, and TPA on paraffin‐embedded tissue blocks of the biopsy samples. Clinical results were validated in a pressurized cell culture system. Interstitial fluid pressures in the tumors (mean 33.5 ± SD 17.2 mmHg) were significantly higher (p = 0.00001) than that in normal tissue (2.9 ± 5.7 mmHg). Pressure readings were significantly higher in low vascularity tumors compared to high vascularity tumors (p < 0.001). In the OS cell lines, growth in a pressurized environment was associated with VEGF‐A downregulation, VEGF‐C upregulation, and TPA upregulation. The reverse was seen in the OB cell line. Growth in the HUVEC cell line was not significantly inhibited in a pressurized environment. Immunohistochemical assessment for VEGF‐A (p = 0.01), VEGF‐C (p = 0.008), and TPA (p = 0.0001) translation were consistent with the findings on PCR. Our data suggests that some molecules in angiogenesis are regulated by changes in IFP. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1520–1525, 2008     

Historical changes in serum PCB and DDT levels in an environmentally-exposed cohort

A previously characterized cohort of 115 Great Lakes fisheaters and 95 non-fisheating controls was re-examined in 1989 to evaluate changes that had occurred in serum PCB and DDT levels since the 1982 study. Substantial and significant decreases in mean serum DDT levels had occurred in both fisheaters (25.8 ppb vs 15.6 ppb) and controls (9.6 ppb vs 6.8 ppb) over this time period. In contrast, only a slight decrease in serum PCB levels was observed, and in fisheaters only. No association between individual changes in serum PCB or DDT levels and self-reported changes in Great Lakes fish consumption was observed. The findings from this longitudinal examination of serum PCB and DDT levels confirm earlier cross-sectional surveys of western populations, and demonstrate that the prohibition of DDT has been successful in reducing the level of DDT contamination in human populations.

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