Acute alterations in anorectal manometry induced by proximal and distal sphincterotomy. Experimental studies on piglets

Anal incontinence causes psychological, social and adaptive troubles prejudicial to the quality of life both in children and adults. Therefore, the detailed knowledge of its causes and the improvement of diagnostic and therapeutic methods increase the possibilities of a more adequate social life to patients with congenital anomalies or sphincteric lesions or degenerations. In this work, a manometric study was developed through an experimental model so as to analyze alterations in behavior of muscle groups responsible for the anorectal sphincteric mechanism, previous to and after proximal and distal lesions. Twenty-two pigs aged between 25 and 30 days, weighing 5-7 kg, were randomly divided into two groups. They were submitted to lesions of different levels in the anorectal muscle. The animals were studied by anorectal manometry (rectoanal inhibitory reflex and vector volume) before and after the lesions. The Student t test and the Wilcoxon test were applied for the statistical analyses, considered p <= 0.05. The proximal lesion preserved sphincter relaxation, retarding its closure [speed of relaxation recovery 4.35 +/- 2.10 vs. 2.70 +/- 1.32 mm/s (p = 0.001)], but it reduced the maximum pressure [62.45 +/- 20.02 vs. 40.36 +/- 12.59 mmHg (p = 0.004)] and vector volume [2,749 +/- 921 vs. 1,591 +/- 1,379 mmHg(2)cm (p = 0.005)]. There was an increment in the high-pressure zone [5.09 +/- 1.04 vs. 6.36 +/- 1.50 mm (p = 0.005)], but the asymmetry percentage and the sphincter length were maintained. The distal lesion did not alter the rectoanal inhibitory reflex, the high-pressure zone length, the asymmetry percentage, or the vector volume. Nevertheless, the sphincter length increased [11.82 +/- 2.82 vs. 14.09 +/- 2.39 mm (p = 0.022)] and the maximum pressure decreased [60.55 +/- 22.05 vs. 40.91 +/- 13.41 mmHg (p = 0.004)]. The alterations observed due to proximal lesion of the anorectal sphincter suggest a direct and more important interference of the levator ani muscle in the function of the sphincteric musculature than that caused by the distal lesion.

THE EFFECT OF DIFFERENT VOLUMES OF ACUTE RESISTANCE EXERCISE ON ELDERLY INDIVIDUALS WITH TREATED HYPERTENSION

Scher, LML, Ferriolli, E, Moriguti, JC, Scher, R, and Lima, NKC. The effect of different volumes of acute resistance exercise on elderly individuals with treated hypertension. J Strength Cond Res 25(4): 1016-1023, 2011-Acute resistance exercise can reduce the blood pressure (BP) of hypertensive subjects. The aim of this study was to evaluate the effect of different volumes of acute low-intensity resistance exercise over the magnitude and the extent of BP changes in treated hypertensive elderly individuals. Sixteen participants (7 men, 9 women), with mean age of 68 6 5 years, performed 3 independent randomized sessions: Control (C: 40 minutes of rest), Exercise 1 (E1: 20 minutes, 1 lap in the circuit), and Exercise 2 (E2: 40 minutes, 2 laps in the circuit) with the intensity of 40% of 1 repetition maximum. Blood pressure was measured before (during 20 minutes) and after each session (every 5 minutes during 60 minutes) using both a mercury sphygmomanometer and a semiautomatic device (Omrom-HEM-431). After that, 24-hour ambulatory blood pressure monitoring was performed (Dyna-MAPA). Blood pressure decreased during the first 60 minutes (systolic: p < 0.01, diastolic: p < 0.05) after all exercise sessions. Only the highest volume session promoted a reduction of mean systolic 24-hour BP and awake BP (p, 0.05) after exercise, with higher diastolic BP during sleep (p, 0.05). Diastolic 24-hour BP and both systolic and diastolic BP during sleep were higher after E1 (p, 0.05). Concluding, acute resistive exercise sessions in a circuit with different volumes reduced BP during the first 60 minutes after exercise in elderly individuals with treated hypertension. However, only the highest volume promoted a reduction of mean 24-hour and awake systolic BP.

OXIDATIVE STRESS BIOMARKER RESPONSES TO AN ACUTE SESSION OF HYPERTROPHY-RESISTANCE TRADITIONAL INTERVAL TRAINING AND CIRCUIT TRAINING

Deminice, R, Sicchieri, T, Mialich, MS, Milani, F, Ovidio, PP, and Jordao, AA. Oxidative stress biomarker responses to an acute session of hypertrophy-resistance traditional interval training and circuit training. J Strength Cond Res 25(3): 798-804, 2011-We have studied circuit resistance schemes with high loads as a time-effective alternative to hypertrophy-traditional resistance training. However, the oxidative stress biomarker responses to high-load circuit training are unknown. The aim of the present study was to compare oxidative stress biomarker response with an acute session of hypertrophy-resistance circuit training and traditional interval training. A week after the 1 repetition maximum (1RM) test, 11 healthy and well-trained male participants completed hypertrophy-resistance acute sessions of traditional interval training (3 x 10 repetitions at 75% of the 1RM, with 90-second passive rest) and circuit training (3 x 10 repetitions at 75% of the 1RM, in alternating performance of 2 exercises with different muscle groups) in a randomized and cross-over design. Venous blood samples were collected before (pre) and 10 minutes after (post) the resistance training sessions for oxidative stress biomarker assays. As expected, the time used to complete the circuit training (20.2 +/- 1.6) was half of that needed to complete the traditional interval training (40.3 +/- 1.8). Significant increases (p < 0.05) in thiobarbituric acid reactive substances (40%), creatine kinase (CK) (67%), glutathione (14%), and uric acid (25%) were detected posttraditional interval training session in relation to pre. In relation to circuit training, a significant increase in CK (33%) activity postsession in relation to pre was observed. Statistical analysis did not reveal any other change in the oxidative stress biomarker after circuit training. In conclusion, circuit resistance-hypertrophy training scheme proposed in the current study promoted lower oxidative stress biomarkers and antioxidant modulations compared with resistance traditional interval training.

High expression of AURKA and AURKB is associated with unfavorable cytogenetic abnormalities and high white blood cell count in patients with acute myeloid leukemia

In the present study, we analyzed AURKA and AURKB gene expression in 70 acute myeloid leukemia (AML) patients. There was no difference between leukemic samples and bone marrow mononuclear cells (BMMCs, n = 8) or CD34(+) progenitors (n = 10) from healthy donors. High white blood cells (WBC) counts were observed in the AURKA(+) and AURKB(+) groups, but no significant differences regarding age, gender, platelet counts or frequency of FLT3-ITD mutations. AURKA, but not AURKB, expression was independently associated with high WBC counts (OR: 3.15, 95% CI 1.07-9.24, p = 0.03). Moreover, the majority of cases that overexpressed AURKA and AURKB presented unfavorable cytogenetic abnormalities (p < 0.001). In conclusion, we described a significant association between overexpression of AURKA/B and cytogenetics findings in AML, which may be relevant to new therapeutic approaches, based on Aurora kinase inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.

Therapeutic Leukapheresis in Patients with Leukostasis Secondary to Acute Myelogenous Leukemia

Leukostasis is a relatively uncommon but potentially catastrophic complication of acute myelogenous leukemia (AML). Prompt leukoreduction is considered imperative to reduce the high mortality rate in this condition. Leukapheresis, usually associated with chemotherapy, is an established approach to diminish blast cell counts. We report a single center experience in managing leukostasis with leukapheresis. Fifteen patients with leukostasis of 187 patients with AML (8.02%) followed at our institution were treated with leukapheresis associated with chemotherapy. The procedures were scheduled to be performed on a daily basis until clinical improvement was achieved and WBC counts were significantly reduced. Overall and early mortalities, defined as that occurred in the first 7 days from diagnosis, were reported. A high proportion of our patients with leukostasis (46.66%) had a monocytic subtype AML (M4/M5, according to French-American-British classification). The median overall survival was 10 days, despite a significant WBC reduction after the first apheresis procedure (from 200.7 X 10(9)/L to 150.3 X 10(9)/L). Almost half of patients (7/15) had an early death. Therapeutic leukapheresis, associated or not to chemotherapy, is an effective approach to reduce WBC counts in patients with AML and leukostasis; however, this therapeutic procedure does not appear to change significantly the sombre prognosis observed in the majority of patients with this complication. Other forms of treatment must be found to reduce the high mortality rate related to leukostasis. J. Clin. Apheresis 26:181-185, 2011. (C) 2011 Wiley-Liss, Inc.

Outcome of acute myeloid leukemia patients with hyperleukocytosis in Brazil

Acute myeloid leukemia (AML) with a high white blood cell (WBC) count at presentation has been associated with an increased early mortality rate, usually secondary to leukostasis. However, the value of the WBC count at which there is a high risk of early death (ED) and the efficiency of supportive treatments remain unclear. In this report, a series of 187 consecutive adult patients with AML in our institution was reviewed. The outcome of 40 patients with WBC above 50 x 10(9) L(-1) (hyperleukocytosis) was compared to 147 patients with a leukocyte count lower than 50 x 10(9) L(-1). The group with hyperleukocytosis showed a significantly shorter OS (P < 0.0001) and a higher rate of ED (P = 0.0008). Even when the data from ED patients were removed from analysis, we still detected a shorter OS in patients with hyperleukocytosis (P = 0.0049), which suggests that high WBC number influences long-term survival, and not only ED. We also observed higher lactic dehydrogenase (LDH) and serum creatinine levels in the group of patients with hyperleukocytosis (P = 0.0003 and 0.0406, respectively). Besides considering all the patients with ED, we could observe higher levels of lactic dehydrogenase, a serum creatinine and nitrogen urea (P = 0.0056, P = 0.0008 and P < 0.0001, respectively). Pulmonary involvement was more frequent in patients with ED (P = 0.0277). In conclusion, hyperleukocytosis confers a poorer prognosis in patients with AML.

Role of Microparticles in the Hemostatic Dysfunction in Acute Promyelocytic Leukemia

Serious bleeding and thrombotic complications are frequent in acute promyelocytic leukemia (APL) and are major causes of morbidity and mortality. Microparticles (MP) have been used to study the risk and pathogenesis of thrombosis in many malignant disorders. To date, from published articles, this approach had not been applied to APL. In this article, the hemostatic dysfunction in this disorder is briefly reviewed. A study design to address this problem using MP is described. MP bearing tissue factor, profibrinolytic factors (tissue plasminogen activator and annexin A2), and the antifibrinolytic factor plasminogen activator inhibitor type 1 were measured using flow cytometry. The cellular origin of the MP was identified by specific cell surface markers. Comparison of the various populations of MP was made between samples collected at the time of diagnosis with those collected at molecular remission. Preliminary data suggest that this approach is feasible.

Blood and Salivary Oxidative Stress Biomarkers Following an Acute Session of Resistance Exercise in Humans

The aim of the present study was to compare oxidative stress biomarkers determined in blood and saliva before and after acute resistance exercise. 1 week after 1 maximum repetition (1RM) test 11 healthy well-trained males completed a hypertrophy acute session of resistance training including 3 sets of 10 repetitions at 75% of the 1RM, with 90s rest periods between sets. Venous blood and saliva samples were collected before (pre) and 10 min after (post) the resistance training session. A significant (p < 0.05) rise in blood lactate accumulation (pre: 1.6 +/- 0.4 vs. post: 9.5 +/- 2.4) was found post-acute resistance training compared with baseline values. Significant increases (p < 0.05) in TBARS (42%), AOPP (28%), uric acid (27%) and GSH (14%) were detected post-acute resistance training in relation to pre in blood samples. A significant increase (p < 0.05) in uric acid (36%) was found in saliva post-acute resistance training as well as a significant correlation (p < 0.05) between uric acid determined in blood and saliva. Statistical analysis did not reveal any other change in the salivary oxidative stress biomarkers. In conclusion, an acute session of resistance exercise induces oxidative stress in plasma of trained men after acute resistance training, which was not found in saliva samples except for uric acid.

Segmental amplification of MLL gene associated with high expression of AURKA and AURKB genes in a case of acute monoblastic leukemia with complex karyotype

We report a case of acute monoblastic leukemia showing a jumping translocation with the MLL gene in a 17-year-old male. Classic cytogenetic and spectral karyotyping revealed a complex karyotype, and fluorescence in situ hybridization (FISH) demonstrated amplification of the MLL gene followed by translocation to chromosomes 15q, 17q, and 19q. In addition, molecular analyses showed a high expression of AURKA and AURKB genes. It is already known that overexpression of Aurora kinases is associated with chromosomal instability and poor prognosis. The formation of jumping translocations is a rare cytogenetic event and there is evidence pointing toward preferential involvement of the heterochromatin region of donor chromosomes and the telomere ends of recipient chromosomes. Jumping translocation with the MLL gene rearrangement is an uncommon phenomenon reported in leukemia cytogenetics. (C) 2010 Elsevier Inc. All rights reserved.

Targeting the Acute Myeloid Leukemia Stem Cells

The idea that within the bulk of leukemic cells there are immature progenitors which are intrinsically resistant to chemotherapy and able to repopulate the tumor after treatment is not recent. Nevertheless, the term leukemia stem cells (LSCs) has been adopted recently to describe these immature progenitors based on the fact that they share the most relevant features of the normal hematopoetic stem cells (HSCs), i.e. the self-renewal potential and quiescent status. LSCs differ from their normal counterparts and from the more differentiated leukemic cells regarding the default status of pathways regulating apoptosis, cell cycle, telomere maintenance and transport pumps activity. In addition, unique features regarding the interaction of these cells with the microenvironment have been characterized. Therapeutic strategies targeting these unique features are at different stages of development but the reported results are promising. The aim of this review is, by taking acute myeloid leukemia (AML) as a bona fide example, to discuss some of the mechanisms used by the LSCs to survive and the strategies which could be used to eradicate these cells.

Genetic polymorphisms involved in folate metabolism and concentrations of methylmalonic acid and folate on plasma homocysteine and risk of coronary artery disease

Objectives Alterations in the enzymes involved in homocysteine (Hcy) metabolism or vitamin deficiency could play a role in coronary artery disease (CAD) development. This study investigated the influence of MTHFR and MTR gene polymorphisms, plasma folate and MMA on Hcy concentrations and CAD development. MMA and folate concentrations were also investigated according to the polymorphisms. Methods Two hundred and eighty-three unrelated Caucasian individuals undergoing coronary angiography (175 with CAD and 108 non-CAD) were assessed in a case-control study. Plasma Hcy and MMA were measured by liquid chromatography/tandem mass spectrometry. Plasma folate was measured by competitive immunoassay. Dietary intake was evaluated using a nutritional questionnaire. Polymorphisms MTHFR and MTR were investigated by polymerase chain reaction (PCR) followed by enzyme digestion or allele-specific PCR. Results Hcy mean concentrations were higher in CAD patients compared to controls, but below statistical significance (P = 0.246). Increased MMA mean concentrations were frequently observed in the CAD group (P = 0.048). Individuals with MMA concentrations > 0.5 mu mol/l (vitamin B(12) deficiency) were found only in the CAD group (P = 0.004). A positive correlation between MMA and Hcy mean concentrations was observed in both groups, CAD (P = 0.001) and non-CAD (P = 0.020). MMA mean concentrations were significantly higher in patients with hyperhomocysteinemia in both groups, CAD and non-CAD (P = 0.0063 and P = 0.013, respectively). Folate mean concentration was significantly lower in carriers of the wild-type MTHFR 1298AA genotype (P = 0.010). Conclusion Our results suggest a correlation between the MTHFR A1298C polymorphism and plasma folate concentration. Vitamin B(12) deficiency, reflected by increased MMA concentration, is an important risk factor for the development both of hyperhomocysteinemia and CAD.

Assessment of Vascular Effects of Tamoxifen and Its Metabolites on the Rat Perfused Hindquarter Vascular Bed

Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30-100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen, and endoxifen) for 2 weeks. Plasma and whole-blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone-based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD(2) = 2.2 +/- 0.06 and 1.9 +/- 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD(2) = 2.5 +/- 0.04 after N-desmethyl-tamoxifen, 2.5 +/- 0.03 after 4-hydroxy-tamoxifen, and 2.6 +/- 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial-independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation.

THE MEDIAL AMYGDALOID NUCLEUS MODULATES CARDIOVASCULAR RESPONSES TO ACUTE RESTRAINT IN RATS

The medial amygdaloid nucleus (MeA) modulates several physiological and behavioral processes and among them, the cardiovascular correlates of behavioral responses to stressful stimuli. Acute restraint evokes cardiovascular responses, which are characterized by both elevated blood pressure (BP) and intense heart rate (HR) increase. We presently report effects of MeA pharmacological manipulations on BP and HR responses evoked by acute restraint in rats. Bilateral microinjection of 100 nL of the unspecific synaptic blocker COCl(2) (1 mM) into the MeA increased HR response to acute restraint, without significant effect on the BP response. This result indicates an inhibitory influence of MeA on restraint-evoked HR changes. Injections of the non-selective muscarinic receptor antagonist atropine (3 nmol); the inhibitor of choline uptake hemicholinium (2 nmol) or the selective M(1)-receptor antagonist pirenzepine (6 nmol) caused effects that were similar to those caused by cobalt. These results suggest that local cholinergic neurotransmission and M(1)-receptors mediate the MeA inhibitory influence on restraint-related HR responses. Pretreatment with the M3 receptor antagonist 4-DAMP (4-Diphenylacetoxy-N-methylpiperidine methiodide-2 nmol) did not affect restraint-related cardiovascular responses, reinforcing the idea that M(1)-receptors mediate MeA-related inhibitory influence on restraint-evoked HR increase. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

The paraventricular nucleus of the hypothalamus is involved in cardiovascular responses to acute restraint stress in rats

The paraventricular nucleus of the hypothalamus (PVN) has been implicated in several aspects of cardiovascular control. Stimulation of the PVN evokes changes in blood pressure and heart rate. Additionally, this brain area is connected to several limbic structures implicated in behavioral control, as well as to forebrain and brainstem structures involved in cardiovascular control. This evidence indicates that the PVN may modulate cardiovascular correlates of behavioral responses to stressful stimuli. Acute restraint is an unavoidable stressor that evokes marked and sustained cardiovascular changes, which are characterized by elevated mean arterial pressure (MAP) and an intense heart rate (HR) increase. We report on the effect of inhibition of PVN synapses on MAP and HR responses evoked by acute restraint in rats. Bilateral microinjection of the nonspecific synaptic blocker cobalt (CoCl2, 1mM/100nl) into the PVN did not change the HR response or the initial peak of the MAP response to restraint stress, but reduced the area under the curve of the MAP response. Moreover, bilateral microinjection of cobalt in areas surrounding the PVN did not change the cardiovascular response to restraint. These results indicate that synapses in the PVN are involved in the neural pathway that controls blood pressure changes evoked by restraint.