Effects of nafazatrom on cardiovascular, sympathetic, and endocrine responses to hemorrhagic shock in conscious rats

Nafazatrom is an antithrombic drug that has been shown to have beneficial effects in traumatic shock and organ ischemia. This study evaluated the effect of nafazatrom on cardiovascular, sympathetic, and endocrine consequences to moderate or severe hemorrhagic shock in the conscious rat. Nafazatrom (2 mg/kg, i.v.) had no effect on the blood pressure, heart rate, and circulatory norepinephrine, vasopressin, and leukotriene C4 responses to bleeding. Nafazatrom significantly reduced plasma TXB2 and 6-keto-PGF1 alpha and blocked the increment in these cyclooxygenase metabolites in response to hemorrhage. It is concluded that nafazatrom does not increase survival after moderate hypovolemic hypotension and decreases survival to severe hemorrhage. Nafazatrom does not modify the cardiovascular, sympathetic, and neuroendocrine responses to hypovolemic hypotension.     

Inhibition of delayed-type contact hypersensitivity in mice deficient in both E-selectin and P-selectin

Leukocyte rolling and emigration in response to inflammatory stimuli appears to involve both E-selectin- and P-selectin-dependent adhesion, which suggests that these molecules have overlapping functions. To clarify their relative contributions in chronic inflammation, we examined delayed-type contact hypersensitivity (DTH) responses in P- selectin, E-selectin, and E-/P-selectin-deficient mice. Oxazolone- induced increases in ear thickness and ear weight were equivalent in wild-type mice and in P-selectin and E-selectin mutants, but were significantly reduced in E-/P-selectin mutants. The number and area of microabscesses on the ears of E-/P-deficient mice were decreased by 72% and 93%, and the number of leukocytes invading the subdermal ear tissue was reduced. T cells from E-/P-deficient mice transferred oxazolone reactivity into naive wild-type mice. However, when donor T cells from wild-type mice were transferred into E-/P-selectin-deficient mice, the DTH response was significantly impaired. These results show that leukocyte recruitment into a subacute inflammatory reaction can occur when either P-selectin or E-selectin is present, but is significantly reduced when both selectins are absent. Both P- and E-selectin are likely to play important roles in the development and maintenance of inflammatory diseases.     

Polymorphism of adhesion molecule CD31 is not a significant risk factor for graft-versus-host disease

Mismatch between bone marrow transplant (BMT) patient and donor for an amino acid polymorphism within the adhesion molecule CD31 has recently been reported to increase risk for the development of graft-versus-host disease (GVHD). We further examined this association in a larger series of 301 BMT patients (227 with grade III/IV GVHD and 74 with grade 0 GVHD) and their HLA-identical sibling donors. CD31 genotypes were determined by polymerase chain reaction and restriction endonuclease digestion. The role of mismatch at the CD31 locus in the development of GVHD was assessed by analyzing the extent of CD31 identity and CD31 compatibility among the grade 0 GVHD and grade III/IV GVHD sibling pairs. No significant association between CD31 mismatch and the development of severe GVHD was detected in our overall patient population. Sixty-three percent of grade III/IV GVHD sibling pairs and 69% of grade 0 GVHD sibling pairs had CD31 genotypes that were identical (P = .36, odds ratio = 1.30). In addition, neither the grade 0 GVHD group (P = .10) nor the grade III/IV GVHD group (P = .27) differed significantly from the expected probability of identity between sibling pairs. Mismatch at the CD31 polymorphism between recipients and donors showed no consistent association with the development of GVHD. Current evidence does not support the value of CD31 mismatch in the selection of BMT donors.     

Roller massage: Comparison of three different surface type pattern foam rollers on passive knee range of motion and pain perception

IntroductionRoller massage with a foam roller has become a common intervention. To date, no studies have examined the therapeutic effects of different surface type rollers. The purpose of this study was to measure the therapeutic effects of three different surface type pattern foam rollers with the same density on passive knee joint range of motion (ROM) and pressure pain threshold (PPT) of the quadriceps.MethodsThis pre-test, post-test randomized controlled trial was conducted in a university laboratory. Thirty-six participants (M = 22, F = 14; mean age = 25.20 ± 4.44 years) were randomly assigned to three groups: (1) smooth surface, (2) multilevel surface, and (3) GRID surface. The intervention was a 2-min rolling session. Outcomes included knee ROM and PPT.ResultsBetween group comparisons revealed a statistically significant post-intervention difference between the three rollers for knee ROM (p = 0.04) and PPT (p < 0.001). Within group comparison for ROM revealed a 3-degree (p = 0.015) increase for the smooth, a 5-degree (p < 0.001) increase for the multilevel, and a 6-degree (p < 0.001) increase for the GRID surface roller. For PPT, there was an increase of 14 kPa (p = 0.562) for the smooth, 179 kPa (p < 0.001) for the multilevel, and 182 kPa (p < 0.001) for the GRID.ConclusionThe GRID and multilevel surface rollers produced greater immediate post-intervention effects than the smooth roller. The therapeutic effects of the GRID and multilevel rollers may be due to the surface architecture. These rollers may provide a greater deformation of the tissues which creates a local mechanical and global neurophysiological effect.     

Breast Cancer Chemoprevention among High‐risk Women and those with Ductal Carcinoma In Situ

Chemoprevention with the anti‐estrogens, tamoxifen, raloxifene, and aromatase inhibitors, reduce breast cancer incidence in high‐risk women; however, uptake has been poor (<5%) in the prevention setting. We assessed use of anti‐estrogens for breast cancer prevention, among high‐risk women seen at an academic breast center, to observe how uptake rates compare in this setting. We collected data on demographics, breast cancer risk factors, and health behaviors via self‐administered questionnaires and medical chart abstraction. Women eligible for chemoprevention with anti‐estrogens had a 5‐year predicted breast cancer risk according to the Gail model of ≥1.67%, history of lobular or ductal carcinoma in situ (LCIS/DCIS), and/or BRCA mutation. We dichotomized anti‐estrogen use as ever or never. Predictors of use were evaluated using multivariable log‐binomial regression. Of 412 high‐risk women enrolled, 316 (77%) were eligible for chemoprevention. Among eligible women, 55% were non‐Hispanic white, 29% Hispanic, 8% non‐Hispanic black, and 7% Asian. Women were grouped based upon their highest category of breast cancer risk (in descending order): BRCA mutation carriers (3%), DCIS (40%), LCIS (22%), and 5‐year Gail risk ≥1.67% (36%). Among those eligible for chemoprevention, 162 (51%) had ever initiated anti‐estrogen therapy (71% tamoxifen, 23% raloxifene, 5% aromatase inhibitor). Anti‐estrogen use was highest among women with DCIS (73%). In multivariable analysis, women with a 5‐year Gail risk ≥1.67% had approximately a 20% lower likelihood of anti‐estrogen use compared to women with DCIS (p = 0.01). In the primary prevention setting, excluding women diagnosed with DCIS, anti‐estrogen use was 37%. Multivariable analysis showed differences in uptake by education and potentially by race/ethnicity. Among high‐risk women seen at a breast center, anti‐estrogen use for chemoprevention was relatively high as compared to the published literature. Clinicians can support high‐risk women by effectively communicating breast cancer risk and enhancing knowledge about the risks and benefits of chemoprevention.     

The effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer

Introduction

Preliminary studies show that device assisted intravesical therapies appear more effective than passive diffusion intravesical therapy for the treatment of non-muscle invasive bladder cancer (NMIBC) in specific settings, and phase III studies are now being conducted. Consequently, we have undertaken a non-systematic review with the objective of describing the scientific basis and mechanisms of action of electromotive drug administration (EMDA) and chemohyperthermia (CHT).

Methods

PubMed, ClinicalTrials.gov and the Cochrane Library were searched to source evidence for this non-systematic review. Randomised controlled trials, systematic reviews and meta-analyses were evaluated. Publications regarding the scientific basis and mechanisms of action of EMDA and CHT were identified, as well as clinical studies to date.

Results

EMDA takes advantage of three phenomena: iontophoresis, electro-osmosis and electroporation. It has been found to reduce recurrence rates in NMIBC patients and has been proposed as an addition or alternative to bacillus Calmette–Guérin (BCG) therapy in the treatment of high risk NMIBC. CHT improves the efficacy of mitomycin C by three mechanisms: tumour cell cytotoxicity, altered tumour blood flow and localised immune responses. Fewer studies have been conducted with CHT than with EMDA but they have demonstrated utility for increasing disease-free survival, especially in patients who have previously failed BCG therapy.

Conclusions

It is anticipated that EMDA and CHT will play important roles in the management of NMIBC in the future. Techniques of delivery should be standardised, and there is a need for more randomised controlled trials to evaluate the benefits of the treatments alongside quality of life and cost-effectiveness.     

Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites

Acute beta-adrenergic stimulation enhances cardiac contractility, accelerates muscle relaxation, and amplifies the inotropic and lusitropic response to increased stimulation frequency. These effects are modulated by phosphorylation of calcium handling and myofilament proteins such as troponin I (TnI) by protein kinase A (PKA). To more directly delineate the role of TnI PKA phosphorylation, transgenic mice were generated that overexpress cardiac TnI in which the serine residues normally targeted by PKA are mutated to aspartic acid to mimic constitutive phosphorylation (TnIDD22,23). Native cardiac TnI was near completely replaced in one transgenic line as assessed by in vitro phosphorylation, and this led to reduced calcium sensitivity of myofibrillar MgATPase, as expected. TnIDD22,23 mice had mildly enhanced basal systolic and diastolic function, and displayed marked augmentation of frequency-dependent inotropy and relaxation, with a peak frequency response 2-fold greater in mutants than controls (P<0.005). Increasing afterload prolonged relaxation more in nontransgenic than TnIDD22,23 (P<0.02), whereas contractile responses to afterload were similar between these strains. Isoproterenol treatment eliminated the differential force-frequency and afterload response between TnIDD22,23 and controls. In contrast to in vivo studies, isolated isometric trabeculae from nontransgenic and TnIDD22,23 mice had similar basal, isoproterenol-, and frequency-stimulated function, suggesting that muscle shortening may be important to TnI PKA effects. These results support a novel role for cardiac TnI PKA phosphorylation in the rate-dependent enhancement of systolic and diastolic function in vivo and afterload sensitivity of relaxation. These results have implications for cardiac failure in which force-frequency modulation is blunted and afterload relaxation sensitivity increased in association with diminished PKA TnI phosphorylation.     

Impaired metabolic modulation of α-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle

The neuronal isoform of nitric oxide synthase (nNOS) is highly expressed in mammalian skeletal muscle, but its functional role has not been defined. NO has been implicated in the local metabolic regulation of blood flow in contracting skeletal muscle in part by antagonizing sympathetic vasoconstriction. We therefore hypothesized that nNOS in skeletal muscle is the source of the NO mediating the inhibition of sympathetic vasoconstriction in contracting muscle. In the mdx mouse, a model of Duchenne muscular dystrophy in which dystrophin deficiency results in greatly reduced expression of nNOS in skeletal muscle, we found that the normal ability of skeletal muscle contraction to attenuate α-adrenergic vasoconstriction is defective. Similar results were obtained in mutant mice that lack the gene encoding nNOS. Together these data suggest a specific role for nNOS in the local metabolic inhibition of α-adrenergic vasoconstriction in active skeletal muscle.     

Protein phosphorylation: quantitative analysis in vivo and in intact cell systems

Protein phosphorylation-dephosphorylation appears to be an essential component in the regulation of many cellular processes by hormones and drugs. This concept has developed primarily from in vitro biochemical studies in which various purified proteins have been phosphorylated and dephosphorylated by distinct protein kinases and phosphoprotein phosphatases. However, the more difficult, but essential, task of demonstrating the physiological occurrence of these reactions in intact tissue or cell preparations in many cases has not been undertaken in a quantitative manner. There are 4 basic approaches for assessing the extent of protein phosphorylation in vivo and in intact cell systems, each having particular advantages and disadvantages. These are summarized in Table 2. The applicability of any one procedure will be highly dependent upon the protein under investigation. For instance, chemical measurements of total protein-bound phosphate may provide only limited information for proteins which are phosphorylated at multiple sites but could be highly useful for those proteins such as glycogen phosphorylase which are phosphorylated at single sites. The relative ease and the high sensitivity of measuring 32P incorporation into proteins will tempt many investigators to rely heavily on this approach. It is a very powerful procedure, particularly for the initial identification of phosphoproteins, but ultimately quantitative conclusions regarding 32P incorporation must be corroborated by one or more of the other procedures. There is no simple, single experimental approach that may be used under all circumstances, but by integrating these procedures firm conclusions may be drawn regarding the physiological importance of phorphorylation of specific proteins.