Accelerated recovery from irradiation injury by angiotensin peptides

PURPOSE: Angiotensin peptides have been shown to affect the proliferation and chemotaxis of multiple cell types. More recent studies in this laboratory have shown that angiotensin II (AII) can increase colony formation and proliferation by hematopoietic progenitors and mesenchymal cells in vitro. As white blood cell (WBC) recovery after bone marrow injury requires progenitor proliferation, the effect of AII and angiotensin (1-7) [A(1-7)], a non-hypertensive fragment of AII, on recovery from total body irradiation was evaluated in C57Bl/6 mice. MATERIALS AND METHODS: The effect of angiotensin peptides on hematopoietic recovery and the number of progenitors in the bone marrow of irradiated C57Bl/6 mice was evaluated. RESULTS: Treatment of animals with angiotensin peptides accelerated hematopoietic recovery and increased the number of hematopoietic progenitors in bone marrow and in the blood. The increase in WBC concentration continued for a longer time after cessation of AII therapy than after treatment with filgrastim. Specifically, the number of WBCs continued to increase 21 days after irradiation with 7 days of angiotensin peptide administration. In contrast, the number of WBCs increased through day 13 with 7 days of filgrastim administration. On day 35 after irradiation (28 days after the last treatment), AII was shown to have increased the number of CFU-GM in the bone marrow of irradiated mice, whereas filgrastim administration had not. Angiotensin peptides also reduced the drop in platelet concentration after irradiation and increased the number of megakaryocyte precursors and megakaryocytes in the bone marrow. Receptor blocking studies indicated that losartan, an antagonist of the angiotensin type 1 receptor, blocked recovery of WBC levels in response to treatment with AII. In contrast, the increase in WBC levels in response to treatment with A(1-7), a ligand for other angiotensin receptors, was not affected by losartan. CONCLUSIONS: These findings suggest that these peptides utilize distinct receptors in the stimulation of hematopoietic recovery. In summary, systemic administration of angiotensin peptides led to an acceleration in hematopoietic recovery after irradiation. These peptides act to stimulate the formation of bone marrow progenitors, thereby facilitating recovery after myelosuppressive irradiation.     

Initial treatment for prostate carcinoma in relation to comorbidity and symptoms

BACKGROUND: Evidence suggests the type of treatment received for prostate carcinoma is associated with comorbidity, but little information is available on associations with specific comorbid disease or symptoms. The authors examined the relations between treatment and comorbidity, specific comorbid disease, and symptoms. METHODS: Medical records were abstracted for 1054 male members of the Kaiser Permanente medical care program diagnosed with prostate carcinoma from 1975 to 1987. Information was obtained on demographic characteristics, comorbid conditions, symptoms, tumor stage and grade, and treatment. Logistic regression was used to determine the significant predictors of treatment (radiation vs. nonaggressive treatment and surgery vs. nonaggressive treatment). RESULTS: Compared to nonaggressive treatment, radiation treatment was less likely among men who had prior cancer (adjusted odds ratio [OR] 0.29, 95% confidence interval [CI] 0.09-0.90) or cerebrovascular disease (OR 0.33, 95% CI 0.13-0.83). There was a significant interaction between race and myocardial infarction (P = 0.02). Surgery, compared to nonaggressive treatment, was less common among men with a prior cancer (OR 0.21, 95% CI 0.07-0.63) or congestive heart failure (OR 0.29, 95% CI 0.09-0.90). Significant interactions were observed between race and myocardial infarction (P = 0.01), diabetes and dysuria or hematuria (P = 0.02), and para- or hemiplegia and urinary frequency or nocturia (P = 0.01). CONCLUSIONS: Specific symptoms and comorbidity appear to influence treatment for prostate carcinoma. More research is needed on treatment differences by race.     

Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo

Cyclooxygenase-2 (COX-2) is expressed within neovascular structures that support many human cancers. Inhibition of COX-2 by celecoxib delays tumor growth and metastasis in xenograft tumor models as well as suppresses basic fibroblast growth factor 2 (FGF-2)-induced neovascularization of the rodent cornea. The present studies were undertaken to evaluate possible mechanisms of the antiangiogenic and anticancer effects of celecoxib. Prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)) were increased in rat corneas implanted with slow-release pellets containing FGF-2 (338.6 ng of PGE(2)/g and 17.53 ng of TXB(2)/g) compared with normal rat corneas (63.1 ng of PGE(2)/g and 2.0 ng of TXB(2)/g). Celecoxib at 30 mg/kg/day p.o. inhibited angiogenesis (78.6%) and prostaglandin production by 78% for PGE(2) (72.65 ng/g) and 68% for TXB(2) (5.55 ng/g). Decreased prostaglandin production in corneas was associated with a 2.5-fold cellular increase in apoptosis and a 65% decrease in proliferation. Similar reductions in proliferation were observed in neovascular stroma (65-70%) of celecoxib-treated (dietary 160 ppm/day) xenograft tumors as well as in tumor cells (50-75%). Apoptosis was also increased in the tumor cells (2.2-3.0-fold) in response to celecoxib. Thus, the antitumor activity of celecoxib may be attributable, at least in part, to a direct effect on host stromal elements, such as the angiogenic vasculature.     

Genetic aberrations defined by comparative genomic hybridization distinguish long-term from typical survivors of glioblastoma

Glioblastoma (GBM) remains a highly lethal neoplasm, refractory to current therapies. The molecular genetic aberrations most closely related to clinical aggressiveness in GBM have been difficult to identify, perhaps due in part to the short survival range observed in cohorts of GBM patients. To address this, we characterized 39 tumors from rare patients (2-5% of all GBM cases) who experienced long-term survival (>3 years) using comparative genomic hybridization as a genome-wide screen. We then compared the frequency and type of aberrations with those in tumors from 24 typical or short-term survivors [STSs (<1.5 years)]. Losses of 9p and 10 and simple gains of chromosome 7 showed at least trends toward increased frequency in the STS group. Additional aberrations, including loss of 6q and gains of 19q and 20q, were significantly more frequent in the STS group. The presence of 19q loss was exclusive to the long-term survivor (LTS) group. Multivariate analyses indicated that 6q loss, 10q loss, and 19q gain were associated with short-term survival (all P < 0.01). The combination of any two of these three aberrations was seen in 16 of 24 STSs but only 1 of 39 LTSs. This comparison of rare LTSs with STSs (typical GBM survivors) identified 6q loss, 10q loss, and 19q gain, particularly when two or more of these were present, as most closely associated with aggressive clinical behavior in GBM. Loss of 19q may be a marker of long-term survival.     

Cellular localization of bursicon using antisera against partial peptide sequences of this insect cuticle-sclerotizing neurohormone

Bursicon is the final neurohormone released at the end of the molting cycle. It triggers the sclerotization (tanning) of the insect cuticle. Until now, its existence has been verified only by bioassays. In an attempt to identify this important neurohormone, bursicon was purified from homogenates of 2,850 nerve cords of the cockroach Periplaneta americana by using high performance liquid chromatography technology and two-dimensional gel electrophoresis. Bursicon bioactivity was found in four distinct protein spots at approximately 30 kDa between pH 5.3 and 5.9. The protein of one of these spots at pH 5.7 was subsequently microsequenced, and five partial amino acid sequences were retrieved. Evidence is presented that two of these sequences are derived from bursicon. Antibodies raised against the two sequences labeled bursicon-containing neurons in the central nervous systems of P. americana. One of these antisera labeled bursicon-containing neurons in the crickets Teleogryllus commodus and Gryllus bimaculatus, and the moth Manduca sexta. A cluster of four bilaterally paired neurons in the brain of Drososphila melanogaster was also labeled. In addition, this antiserum detected three spots corresponding to bursicon in Western blots of two-dimensional gels. The 12-amino acid sequence detected by this antiserum, thus, seems to be conserved even among species that are distantly related.     

Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study

BACKGROUND: Previous analyses from the Cache County (UT) Study showed inverse associations between the prevalence of AD and the use of nonsteroidal anti-inflammatory drugs (NSAID), aspirin compounds, or histamine H(2) receptor antagonists (H(2)RA). The authors re-examined these associations using data on incident AD. METHODS: In 1995 to 1996, elderly (aged 65+) county residents were assessed for dementia, with current and former use of NSAID, aspirin, and H(2)RA as well as three other "control" medication classes also noted. Three years later, interval medication histories were obtained and 104 participants with incident AD were identified among 3,227 living participants. Discrete time survival analyses estimated the risk of incident AD in relation to medication use. RESULTS: AD incidence was marginally reduced in those reporting NSAID use at any time. Increased duration of use was associated with greater risk reduction, and the estimated hazard ratio was 0.45 with >/=2 years of exposure. Users of NSAID at baseline showed little reduction in AD incidence, regardless of use thereafter. By contrast, former NSAID users showed substantially reduced incidence (estimated hazard ratio = 0.42), with a trend toward greatest risk reduction among those with extended exposure. Similar patterns appeared with aspirin but not with any other medicines examined. CONCLUSIONS: Long-term NSAID use may reduce the risk of AD, provided such use occurs well before the onset of dementia. More recent exposure seems to offer little protection. Recently initiated randomized trials of NSAID for primary prevention of AD are therefore unlikely to show effects with treatment until participants have been followed for several years.     

Education, wealth, and cognitive function in later life

Population-based studies of health often use education as the sole indicator of socioeconomic status (SES); the independent contributions of education and other SES covariates are rarely delineated. Using Wave 1 of the Asset and Health Dynamics Among the Oldest Old study, the authors examined the extent to which educational attainment influences performance on three separate domains of cognitive status by race and Latino ethnicity and introduced controls for wealth and household income. Results indicate that the education effect is minimally weakened after adjusting for wealth; the wealth effect, however, is greatly attenuated after adjusting for education. Blacks and Whites exhibited a similar education--cognition relationship; Latino elderly did not experience commensurate gains in cognitive function with increasing education. Results suggest that although the education--cognition relationship may in part reflect an SES gradient, the association is more likely due to the process and consequences of education itself.     

Perception of intrinsic and extrinsic respiratory loads in children with life-threatening asthma

There is a subpopulation of asthmatic patients with a history of life-threatening asthma (LTA) who have a reduced perception of respiratory loads. The aim of this study was to determine if these patients have a reduced perception of both intrinsic and extrinsic loads. Children with asthma were classified into life-threatening asthma and control asthmatic groups. Perception of extrinsic loads was assessed by magnitude estimation of inspiratory resistive loads. Magnitude estimation was measured with handgrip estimation of resistive load magnitude. Perception of intrinsic loads was by methacholine bronchoprovocation in doses sufficient to a drop to 40% below baseline of forced expired volume in 1 sec (FEV(1)). Chest tightness, breathlessness, and air hunger, as estimated by a Borg scale were, used to rate methacholine perception. Life-threatening asthma subjects had a lower slope than nonlife-threatening asthma subjects for magnitude estimation of resistive loads. Life-threatening asthma patients also had a lower maximum Borg score for all three symptoms. There was no significant difference in magnitude estimation of symptom type.These results suggest that life-threatening asthma subjects have poor perception of extrinsic and intrinsic loads. This suggests that there is a similarity between the sensations elicited by intrinsic and extrinsic loads, allowing for the identification of poor-perceiving patients with either method of assessment and who suffer from life-threatening asthma.     

Pruritic linear papules on a 75-year-old woman: a case of localized Darier-White disease

Darier-White disease (DWD), commonly called Darier disease or keratosis follicularis, is a genodermatosis seen in clinical practice. It exists more commonly in the generalized form but can present as a localized condition. Localized DWD is a rare entity characterized by epidermal changes that are like those seen in the generalized form but that are confined to a small area of skin. This entity is postulated to result from a postzygotic mutation and has the potential to be transmitted to offspring, which may result in the severe generalized form. We report a case of localized DWD diagnosed after biopsy of a recalcitrant linear dermatitis and discuss the salient features of this condition.