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Postepy Hig Med Dosw. (online), 2008; 62: 241-248
Original ArticleFull Text PDF
Megakaryocytes and platelets in experimentally induced renovascular hypertension (2K1C) in rats
Megakariocyty i płytki w doświadczalnym nadciśnieniu naczyniowo–nerkowym (2K1C) u szczurów
Authors' Contribution:
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection
Wstęp: Nadciśnienie tętnicze należy do najczęściej występujących chorób na świecie. U około 10% populacji osób z nadciśnieniem tętniczym ma ono charakter wtórny. Celem badań była ocena układu megakariocytarno-płytkowego w przebiegu nadciśnienia naczyniowo-nerkowego.
Materiał/metody: Wykorzystano model doświadczalny nadciśnienia u szczurów wg Goldblatta (2-kidney, 1-clip). Materiał do badań (krew, szpik kostny) pobierano w 4, 8 i 16 tygodniu eksperymentu. Za pomocą metod immunohistochemicznych i morfometrycznych oceniono megakariocyty szpikowe (MKs). Analizy płytek krwi dokonano w oparciu o ich liczbę (PLT) i średnią objętość (MPV). Oceniono osoczowe stężenie trombopoetyny (TPO).
Wyniki: Przeprowadzone badania wykazały wzrost liczby megakariocytów po 16 tygodniach od zabiegu częściowego podwiązania tętnicy nerkowej. Zmianom towarzyszyły: istotny statystycznie wzrost PLT, masy płytkowej, liczby nagich jąder MKs (NK) oraz zwiększenie wartości współczynnika kształtu jądra (CDN). MPV i osoczowe stężenie TPO nie uległy zmianie podczas eksperymentu . Wykazano istotną dodatnią korelację między wzrostem ciśnienia tętniczego a liczbą MKs i NK. Liczba MKs korelowała dodatnio z PLT i CDN. Mimo że stężenie TPO w osoczu nie uległo znaczącej zmianie, wykazano istotną ujemną korelację między osoczowym stężeniem TPO a PLT.
Dyskusja: Na podstawie przeprowadzonych badań, mimo że nie zaobserwowano cech wzmożonego obrotu płytkowego, można przypuszczać, iż w przebiegu nadciśnienia naczyniowo-nerkowego dochodzi do zmian w układzie megakariocytarnym. Może to rzutować na wytwarzanie płytek krwi i przyczyniać się do rozwoju ewentualnych powikłań nadciśnienia.
Materiał/metody: Wykorzystano model doświadczalny nadciśnienia u szczurów wg Goldblatta (2-kidney, 1-clip). Materiał do badań (krew, szpik kostny) pobierano w 4, 8 i 16 tygodniu eksperymentu. Za pomocą metod immunohistochemicznych i morfometrycznych oceniono megakariocyty szpikowe (MKs). Analizy płytek krwi dokonano w oparciu o ich liczbę (PLT) i średnią objętość (MPV). Oceniono osoczowe stężenie trombopoetyny (TPO).
Wyniki: Przeprowadzone badania wykazały wzrost liczby megakariocytów po 16 tygodniach od zabiegu częściowego podwiązania tętnicy nerkowej. Zmianom towarzyszyły: istotny statystycznie wzrost PLT, masy płytkowej, liczby nagich jąder MKs (NK) oraz zwiększenie wartości współczynnika kształtu jądra (CDN). MPV i osoczowe stężenie TPO nie uległy zmianie podczas eksperymentu . Wykazano istotną dodatnią korelację między wzrostem ciśnienia tętniczego a liczbą MKs i NK. Liczba MKs korelowała dodatnio z PLT i CDN. Mimo że stężenie TPO w osoczu nie uległo znaczącej zmianie, wykazano istotną ujemną korelację między osoczowym stężeniem TPO a PLT.
Dyskusja: Na podstawie przeprowadzonych badań, mimo że nie zaobserwowano cech wzmożonego obrotu płytkowego, można przypuszczać, iż w przebiegu nadciśnienia naczyniowo-nerkowego dochodzi do zmian w układzie megakariocytarnym. Może to rzutować na wytwarzanie płytek krwi i przyczyniać się do rozwoju ewentualnych powikłań nadciśnienia.
Słowa kluczowe: megakariocyty • płytki krwi • nadciśnienie naczyniowo-nerkowe • szczury
Introduction: Hypertension is one of the most frequently occurring diseases worldwide. Approximately 10% of the population with hypertension reveals the secondary type of the disease. The aim of the study was to evaluate the megakaryocyte-platelet system in the course of renovascular hypertension.
Material/Methods: An experimental model of hypertension in rats according to Goldblatt was used in the study. The experimental material (blood, bone marrow) was collected in the 4th, 8th, and 16th weeks of the study. Bone marrow megakaryocytes (MKs) were evaluated using immunohistochemical and morphometric methods. Blood platelets were analyzed based on their count (PLT) and mean volume (MPV). Plasma thrombopoietin (TPO) concentration was also assessed.
Results: The investigation showed increased numbers of MKs 16 weeks after partial unilateral ligation of the renal artery. Statistically significant increase in platelet count, platelet mass, and the number of MK naked nuclei (NKs) as well as elevation of the circular deviation of the nuclei (CDN) of MKs accompanied the changes. MPV and TPO concentration did not change during the experiment. There was significant positive correlation between the increase in blood pressure and the numbers of MKs and NKs. The number of MKs correlated positively with PLT and CDN. Although TPO plasma level did not change significantly, there was marked negative correlation between plasma TPO concentration and PLT.
Conclusions: Although features of intensified platelet turnover were not observed, on the basis of the study it can be assumed that the megakaryocytic system undergoes changes in the course of renovascular hypertension. This can contribute to blood platelet production and the development of possible hypertension complications.
Material/Methods: An experimental model of hypertension in rats according to Goldblatt was used in the study. The experimental material (blood, bone marrow) was collected in the 4th, 8th, and 16th weeks of the study. Bone marrow megakaryocytes (MKs) were evaluated using immunohistochemical and morphometric methods. Blood platelets were analyzed based on their count (PLT) and mean volume (MPV). Plasma thrombopoietin (TPO) concentration was also assessed.
Results: The investigation showed increased numbers of MKs 16 weeks after partial unilateral ligation of the renal artery. Statistically significant increase in platelet count, platelet mass, and the number of MK naked nuclei (NKs) as well as elevation of the circular deviation of the nuclei (CDN) of MKs accompanied the changes. MPV and TPO concentration did not change during the experiment. There was significant positive correlation between the increase in blood pressure and the numbers of MKs and NKs. The number of MKs correlated positively with PLT and CDN. Although TPO plasma level did not change significantly, there was marked negative correlation between plasma TPO concentration and PLT.
Conclusions: Although features of intensified platelet turnover were not observed, on the basis of the study it can be assumed that the megakaryocytic system undergoes changes in the course of renovascular hypertension. This can contribute to blood platelet production and the development of possible hypertension complications.
Key words: megakarycytes • blood platelets • renovascular hypertension • rats
Hypertension is one of the most common diseases worldwide. Along with diabetes mellitus, lipid balance disturbances, smoking, and obesity, it is a significant risk factor of atherosclerosis, cardiovascular diseases such as coronary heart disease, brain stroke, peripheral artery disease, and their direct complications (heart failure, renal failure, encephalopathy). Renovascular hypertension is the most frequent cause of secondary hypertension with potentially removable cause [9]. The complications of hypertension are related to, among others, a hypercoagulative state and a tendency for the formation of thrombi [24,33]. Blood platelets play an important role in these events, in addition to their role in coagulation and fibrinolysis [4,33].
Blood platelets are un-nucleated structures of discoid shape produced as a result of megakaryocyte (MK) cytoplasm fragmentation [17]. Platelets' morphological and functional properties are conditioned during MK development [54]. The influence of various factors on megakaryocytopoiesis is reflected in the function and amount of circulating platelets [54]. Platelets and megakaryocytes create the system of a regulative circle, described as the megakaryocyte-platelet hemostatic axis (MPHA) [37,38,54]. The system is regulated mainly by thrombopoietin (TPO) [11,42]. TPO is a key cytokine which controls the stages leading eventually to the formation of fully mature MKs and enables the formation of the suitable number of platelets [10,11]. The influence of TPO on megakaryocytopoiesis is reflected by the elevated number of MKs and their progenitors in the bone marrow and spleen, MK size, nuclear ploidy (chromosomal DNA content), cytoplasm maturation, intensification of the expression of cellular differentiation markers, and the increase in pro-platelet formation by MKs [11,16,48]. MKs' size and their ploidy correlate directly with the circulating platelet mass, which is the product of the platelet number and mean platelet volume (MPV) [2,12,39]. After thrombocytopenia is induced, the first detectable change is an increase in ploidy and MK size [22,60]. MK number is elevated in a later period [60] and depends on the inflow of their progenitor cells [1,59].
Platelets are a heterogenic blood corpuscle population as far as their size and reactivity are concerned [14,54]. An inverse relationship was observed between platelet number and size [2,60]. It was shown that large platelets were hyper-reactive [2,14,60]. Such changes in platelet volume and function could be related to the release of young platelets or the effects of humoral factors that influence megakaryocytopoiesis regulation and platelet production and function [53,54]. It is assumed that MKs with high ploidy are the source of large hyper-reactive platelets and the increase in platelet volume is the effect of changes in MK cytoplasm fragmentation [54]. The size of platelets and their functional potential are determined in MKs during thrombopoiesis. Platelet size in the circulation does not undergo significant changes [2,35,55]. The physiological mechanisms that regulate platelet volume are not yet known. However, it is known that disturbances concerning both MK and platelet ionic canals are the background of these mechanisms [2]. Changes in platelet mass, involving an imbalance between the number of platelets and their volume, are observed under certain pathological conditions. Thus it seems that platelet number and volume undergo independent regulation [2,55].
In cases of atherosclerotic renal artery narrowing [2,3], diabetes mellitus [52], unstable angina, and myocardial infarction [46,60], normal or increased numbers of large platelets were observed. Patients after myocardial infarction showed increased MPV, which is a predictor of a subsequent ischemic incident. MPV did not correlate with other known vascular diseases risk factors. This suggests that MPV is an independent risk factor of a next acute coronary syndrome [2,54]. On the other hand, in the course of acute ischemic brain stroke, MPV increase was accompanied by a drop in blood platelet number [2,35]. MPV elevation was also observed in patients with hypertension, but the platelet number was normal or lowered [33,38]. It is now known that large hyper-reactive platelets contribute to the development of atherosclerosis [54]. The occurrence of such platelets in prothrombotic conditions is explained as a consequence of the elevated use of corpuscles and their accelerated production [54]. In atherosclerosis- induced diseases, both large and hyper-reactive platelet numbers as well as MK ploidy increase were observed [5,54,55,60]. Similar changes were also presented in diabetes [5] and primary hypertension [38].
So far, the evaluation of the megakaryocyte-platelet system in the course of renovascular hypertension, one of the secondary types of hypertension, has not been performed. In the present study a morphometric evaluation of bone marrow megakaryocytes (count, cell and nuclear size, nuclearcytoplasmic ratio, and the circular deviation of the cells and their nuclei) was performed. We also analyzed blood platelets based on their count and mean volume. Moreover, the assessment of plasma TPO concentration was taken into consideration. In order to analyze the dynamics of possible changes in the megakaryocyte-platelet system, the study material was collected 4, 8, and 16 weeks after surgical narrowing of the renal artery. Blood pressure measurements were also conducted at the same intervals.
Animals and induction of renovascular hypertension
Male Wistar rats (180–220 g) were used in the experiment. A two-kidney one-clip model of hypertension was induced by partial standardized clipping of the left renal artery under pentobarbital anesthesia (40 mg/kg, i.p.). The animals were divided into six groups (Table 1). The rats were then left untouched for the next 4, 8, or 16 weeks. A sham-operated groups of rats (animals that received the same surgical intervention except for the clipping of the artery) served as the controls. During the operation all the animals obtained lincomycin to prevent infection.
Table 1. Division of rats into groups in relation to the time of material collection after the surgical procedure
Blood pressure measurement
Systolic and mean blood pressure were measured in conscious rats by a tail-cuff method (Harvard Rat Tail Pressure Monitor System) according to the method described by R. Zatz [58].
Hematological and biochemical analyses
The blood samples for these analyses were obtained from the living animals, from the study and control groups at 4, 8, and 16 weeks of the experiment. Venous blood was taken without stasis from the right ventricle of the beating heart into the vacutainers containing EDTA for platelet count (PLT) and sodium citrate (4:1) for MPV. Samples of the blood for estimation of TPO plasma levels were also obtained. During this procedure the animals were under pentobarbital anesthesia (40 mg/kg, i.p.) and the thoracic cavity was opened. PLT and MPV were measured by an autocounter. Moreover, platelet mass was calculated according to the formula PLT x MPV [2] for each sample. The blood samples for TPO level estimation were centrifuged immediately and the plasma was stored in several aliquots at -85°C until assayed. Thrombopoietin was assayed by sandwich-type ELISA (Santa Cruz Biotechnology, Inc.; TPO (N-19): sc-1298).
Analysis of bone marrow megakaryocytes
Experimental material
After the rats were sacrificed, the femur and sternum were removed, fixed in 10% buffered formalin, decalcified, and embedded in paraffin.
Staining procedure
Two 5-µm-thick longitudinally oriented bone marrow sections were removed from each sample of both the femur and sternum. One section each from the femur and sternum were stained with hematoxylin-eosin (HE) for complex morphometric analysis of MKs. Other sections (one from the femur and one from the sternum) were prepared for immunohistochemistry. The monoclonal antibody CD61 (clone Y2/51, catalog no. M 0753, DAKO) was used to identify glycoprotein IIIa (GPIIIa). The aim of this examination was to identify, for numerical analysis not only large mature MKs, but also the small young MKs that may be mistaken for other cells.
Following HE staining and immunostaining, morphometric evaluation was performed using an Olympus BX41 microscope with a digital camera connected to a computer in which a standard morphometric program (Micro Image IncD UDF Packed Writing Software for Windows, OLYMPUS) was installed. To estimate the number of MKs and naked nuclei (NKs), i.e. megakaryocytes after the loss of cytoplasm transformed to thrombocytes, the immunohistochemical sections were analyzed. Three randomly selected fields in each section were chosen at a magnification 240× (only areas containing well-preserved hematopoietic tissue were accepted). Only nuclear MKs were included (NKs formed a separate group) [50].
For morphological analysis, HE-stained sections were used. In each section, MKs were identified as cells with diameters >=20 µm and visible nuclei [23]. The following parameters were evaluated in the study: the area of the cell (AC), the area of the nucleus (AN), the nuclear-cytoplasmic ratio (N/C), and the circular deviation (CD) of both MKs (CDC) and their nuclei (CDN). The circular deviation is defined as CD=4πA/C2 (C – circumference, A – surface area), giving the value of 1.0 for a circular shape and a lower factor for irregular outline [50]. The ratio of nuclear material to cytoplasm (N/C) is high in MKs without granulation (less mature MKs) and tends to decrease as granulation increases (more mature MKs) [41]. The N/C ratio was calculated from the quotient of AN and AC. Three randomly selected fields in each section were chosen at a magnification of 480× (only areas containing well-preserved hematopoietic tissue were accepted) and suitable MKs and their nuclei were measured. Then the median values of the parameters were calculated.
We obtained permission from the local ethics committee to perform the investigations on the animals (no. 1004/36).
Statistical analysis
The Statistica PL program was used for the statistical analysis of the results. Minimum, maximum, mean, and standard deviation (SD) were determined for the particular parameters. The evaluation of distribution normality was performed using the Shapiro-Wilk test. The results underwent analysis of variance ANOVA. The significance of differences between groups were estimated with the Tukey-Kramer test and correlation assessment was conducted using the linear correlation test according to Pearson.
Systolic blood pressure (SBP), mean blood pressure (MBP)
SBP values in all the study groups (E1: 135.8, E2: 150.5, E3: 157.0 mmHg) were statistically significantly higher than in the control groups (C1: 116.2, C2: 124.7, C3: 127.3 mmHg, p<0.01). The same was true for MBP (E1: 100.4, E2: 117.0, E3: 119.8 mmHg) compared with the controls (C1: 81.3, C2: 101.7, C3: 102.1 mmHg). SBP values correlated positively with both MK number (p<0.05, r=0.337) and the number of NKs (p<0.05, r=0.371).
Megakaryocytes and blood platelets
The first changes in the megakaryocyte-platelet system were observed in the 8th week after partial renal artery ligation; however, they were statistically insignificant. They concerned decreases in MK and NK counts in the bone marrow and PLT in the blood compared with the control group as well as with the study group evaluated in the 4th week. The megakaryocyte-platelet system showed significant changes in the 16th week of the study. At that time, E3 presented elevated MK and NK numbers in the bone marrow with accompanying increased PLT, platelet mass, and CDN compared with the control group and the study groups assessed earlier (E1, E2; Table 2, Figure 1).
Figure 1. Rat bone marrow section. Loosely oriented megakaryocytes immunostained for CD61 (GP IIIa) to identify cells (group E3) (magnification: 480×)
Table 2. Megakaryocyte and platelet parameters and plasma thrombopoietin concentration in the study and control groups of rats
MK number correlated positively with both PLT (p<0.05, r=0.477) and platelet mass (p<0.01, r=0.557). Moreover, positive correlation was found between the number of MKs and CDN (p<0.05, r=0.467). There was also positive correlation between PLT and platelet mass (p<0.001, r=0.922) and PLT and NK (p<0.05, r=0.434). On the other hand, we did not find changes in MKs size (AC) and MPV, MK nuclear size (AN), or the values of the nuclear-cytoplasmic ratio (N/C) and circular deviation of MKs (CDC) at the particular stages of the study.
TPO plasma level
In the study rats, plasma TPO concentration, although it did not show any significant changes, oscillated in accordance with the regulating mechanism determined by platelet mass, i.e. in the 8th week an increasing tendency of TPO concentration was found in comparison with the values obtained in the controls and the first study group (E1), while in the 16th week a decreasing tendency of TPO level was observed (Table 2). Moreover, negative correlation was observed between plasma TPO concentration and PLT (p<0.05, r=–0.4305) and platelet mass (p<0.01, r=–0.5306).
Hypertension is a disease in the course of which morphological and functional changes of various organs occur. This happens due to both the unfavorable influence of increased blood pressure on vascular walls and pathogenic factors. Hypertensive complications are connected, among others, with hypercoagulability and a tendency for thrombus formation. Besides the coagulative system and fibrinolysis, blood platelets play an important role in these events. Both experimental and clinical studies on hypertension have paid much attention to the evaluation of blood platelets. Only a few of them concerned MKs [1,38]. However, the cells were evaluated under conditions of primary hypertension and not renovascular hypertension, which is a secondary hypertension. As opposed to primary hypertension, the causes of which have not yet been fully determined, the etiology of secondary hypertension is well established.
The pathogenesis of renovascular hypertension is complex. The hemodynamically significant narrowing of a renal artery or arteries leads to kidney hypoperfusion and an increase in plasma renin-angiotensin system (RAS) activity. Afterwards, the activation of tissue RAS, overstimulation of the sympathetic nervous system (SNS), and increased aldosteron (ALDO) and vasopressin (VSP) synthesis and release take place. These factors contribute to the maintenance of increased blood pressure, mainly in the chronic phase of renovascular hypertension. The duration of the particular phases of renovascular hypertension is variable. In rat studies it was observed that the acute phase developed from 2 to 4 weeks and the chronic phase, 9 weeks after partial unilateral ligation of the renal artery [26,32].
In the present study, the first changes in the megakaryocyte- platelet system were observed only 16 weeks after renal artery ligation, i.e. during the time of the chronic phase of renovascular hypertension in rats. The significant elevation of MK number in the bone marrow was found with a simultaneous, slightly decreased concentration of the main factor stimulating megakaryocytopoiesis, i.e. TPO. It is possible that ALDO and/or VSP, factors included in the pathogenesis of renovascular hypertension, had their effect on bone marrow. The results of some studies pointed to the potentially stimulating influence of these factors on megakaryocytic cell-line growth [7,19,27,28,47]. Some studies revealed a stimulating influence of SNS on hematopoietic progenitor cells, including a megakaryotic cell line [20,25,34]. Increased RAS activation could possibly occur in bone marrow, which contributed to the effect. In some studies concerning the issue, Haznedaroglu's hypothesis on tissue RAS functioning in bone marrow was confirmed [18]. It was shown that angiotensin II, through AT1 receptors, stimulated the proliferation of the progenitor cells of various hemopoietic cell lines, including megakaryocytic cells [44].
It should be stressed that hypertension is a factor contributing to the development of atherosclerosis. In previous studies it was observed that in the course of diseases with atherosclerotic etiology, such as coronary disease (especially unstable angina), myocardial infarction, or ischemic brain stroke, large hyper-reactive platelets are produced, which can be accompanied by an increase in platelet mass [2,35,46]. This is a consequence of significantly elevated platelet use and, as a result, their increased production. Thus elevated platelet turnover occurs. In such a situation, the occurrence of large platelets with accompanying changes in MKs (ploidy increase and MK size in the bone marrow) were observed [13,54].
There is an opinion that MKs with abundant cytoplasm are a source of platelets with increased MPV [6,13,54]. However, the mechanism of large platelet formation has not yet been established. It could be the result of changes in MK cytoplasm fragmentation and the effects of cytokines on the process [13,54]. Therefore, suspecting possible changes of MPV, we analyzed not only MK size, but also nuclear-cytoplasmic ratios and the circular deviation of these cells. Other studies on essential thrombocytemia observed, besides the elevation of platelet count and increased mean volume, also the occurrence of MKs of very irregular shape [40,45]. However, CDC did not change during the experiment, which can indirectly explain the lack of MPV changes. It can be assumed that the study rats did not reveal intensive peripheral platelet turnover, which occurs in acute vascular incidents where a thrombus is formed in sites of atheromatous plaque rupture and ulceration [56]. This could be the effect of a lack of advanced atherosclerotic lesions in the blood vessels of experimental animals. Bath et al. observed positive correlation between MPV and the degree of atherosclerosis-induced renal artery narrowing [3].
According to the inverse relationship between MPV and PLT occurring in physiological conditions expressed by the constant product of the values [55], we expected platelet number to be constant provided that MPV was at a constant level. However, PLT unexpectedly increased significantly at the end of the experiment, i.e. after 16 weeks. A positive correlation between MK number and PLT was found, which shows that the PLT changes in rats with experimental renovascular hypertension corresponded with the bone marrow MK numbers. Senaran et al. observed, besides an MPV increase, the co-occurrence of PLT elevation and plasma TPO concentration. The relationship concerned patients with myocardial infarction and unstable angina, which are diseases with an atherosclerotic background with increased platelet turnover [46]. In our study, however, we did not evaluate the morphology of arteries with regard to atherosclerotic lesions, although it seems that such an examination could provide more information. We cannot exclude that TPO could be one of the factors that contributed to the effect observed by Senaran and revealed by our study. In the study rats, plasma TPO concentration did not undergo significant changes but varied in accordance with the regulating mechanism by platelet mass. Moreover, negative correlation was observed between plasma TPO concentration and PLT and platelet mass. The results confirmed the assumption that rats with renovascular hypertension do not show intensified peripheral platelet turnover.
In the 16th week of the experiment, besides the increase in PLT, platelet mass, and MK number, an elevation of NK number in the bone marrow was observed. The increase in NK number (remnants of MKs which released pro-platelets and platelets into the circulation) showed that the main site of platelet production could be the bone marrow vascular sinuses. Positive correlation between NK count and PLT was shown. Of the evaluated morphological parameters of MKs in rats with renovascular hypertension, CDN was significantly elevated. This shows that the MK nuclei had a more regular circumference, which is a feature of less mature MKs compared with MKs of more advanced maturation with multilobular nuclei of irregular circumference [23,41]. Young MKs are also characterized by a high value of N/C. However, mean N/C and MK size did not change in the course of the experiment. It should be considered that, according to Levine [23], the nuclear circumference of MKs that are in the last stage of maturation can become more regular than those in intermediate stages of maturation. The positive correlation between MK number and CDN found in the study can indicate that a marked part of the MK pool consisted of both young cells and MKs in the last stage of maturation, in which the formation and release of cells take place. The increased MK count and PLT in the last stage of the experiment could be a compensative reaction to earlier changes in the megakaryocyte- platelet system, the decreasing tendency of PLT observed in the 8th week of the study. Humoral and neurogenic factors included in the pathogenesis of the chronic phase of renovascular hypertension could participate in the condition.
On the other hand, it should be remembered that the changes in the megakaryocyte-platelet system observed in the 16th week (the last stage of the experiment) could be connected with the longer duration of hypertension and its higher values. This could contribute to the induction of atherosclerotic changes in vessels. Morshita et al., examining the abdominal part of the aorta of rats with hypertension induced by the Goldblatt method (2K1C), observed the presence of hypertrophy and thickening of the vessel wall and an elevation of wall-to-lumen ratio [31]. It can be assumed that in animals with experimental renovascular hypertension examined to evaluate the megakaryocyte- platelet system, the increase in platelet release was the reaction to so-called corpuscle use. Such factors as the elevation of shear stress, endothelial dysfunction/ damage, RAS activation, and the influence of vasopressin could contribute as well [15,21,29,36,43,49,51,57]. In the study rats the process was not intensified, as MPV increase and MK size elevation (which reflects their ploidy) were not observed in the study.
On the basis of this study, although the features of intensified platelet turnover could not be observed it can be assumed that in the course of renovascular hypertension, the megakaryocyte-platelet system undergoes changes. This can contribute to blood platelet production and the development of possible hypertension complications. Previous studies on a similar experimental model showed intensified platelet aggregation induced using ADP compared with rats of a control group [8,30]. The evaluation of advancement stage of atherosclerotic changes and humoral factors related to their occurrence in rats with experimental renovascular hypertension need to be explained.
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[19] Hunt N.H., Perris A.D., Sandford P.A.: Role of vasopressin in the mitotic response of rat bone marrow cells to haemorrhage. J. Endocrinol., 1977; 72: 5-16
[20] Katayama Y., Battista M., Kao W.M., Hidalgo A., Peired A.J., Thomas S.A., Frenette P.S.: Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell, 2006; 124: 407-421
[PubMed] [Full Text HTML] [Full Text PDF]
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[21] Kher N., Marsh J.D.: Pathobiology of atherosclerosis - a brief review. Semin. Thromb. Hemost., 2004; 30: 665-672
[22] Kuter D.J., Rosenberg R.D.: Regulation of megakaryocyte ploidy in vivo in the rat. Blood, 1990; 75: 74-81
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[PubMed] [Full Text PDF]
[23] Levine R.F., Hazzard K.C., Lamberg J.D.: The significance of megakaryocyte size. Blood, 1982; 60: 1122-1131
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[PubMed] [Full Text PDF]
[24] Lominadze D., Joshua I.G., Schuschke D.A.: In vivo platelet thrombus formation in microvessels of spontaneously hypertensive rats. Am. J. Hypertens., 1997; 10: 1140-1146
[25] Maestroni G.J.: Neurohormones and catecholamines as functional components of the bone marrow microenvironment. Ann. N Y Acad. Sci., 2000; 917: 29-37
[26] Martinez-Maldonado M.: Pathophysiology of renovascular hypertension. Hypertension, 1991; 17: 707-719
[27] Mirshahi M., Valamanesh F., Golestaneh N., Mirshahi P., Vincent L., Tang R., Agarwal M.K.: Mineralocorticoid hormones exert dramatic effects on pluripotent human stem cell progeny. Int. J. Toxicol., 2003; 22: 297-304
[28] Miszta H., Kasprzykowski F., Grzonka Z., Lankiewicz L.: Effect of vasopressin, oxytocin and LHRH on the proliferation and metabolism of rat bone marrow stromal cells in culture. Endocr. Regul., 1991; 25: 177-180
[29] Mogielnicki A., Chabielska E., Pawlak R., Szemraj J., Buczko W.: Angiotensin II enhances thrombosis development in renovascular hypertensive rats. Thromb. Haemost., 2005; 93: 1069-1076
[30] Morelowska D., Chabielska E., Pawlak D., Azzadin A., Bialkowska A., Krygicz D., Buczko W.: Effect of captopril on serotonergic mechanisms in two-kidney, one-clip renal hypertensive rats. Pol. J. Pharmacol. Pharm., 1992; 44: 365-372
[31] Morishita R., Higaki J., Miyazaki M., Ogihara T.: Possible role of the vascular renin-angiotensin system in hypertension and vascular hypertrophy. Hypertension, 1992; 19: II62-67
[32] Morton J.J., Wallace E.C.: The importance of the renin-angiotensin system in the development and maintenance of hypertension in the two-kidney one-clip hypertensive rat. Clin. Sci. (Lond), 1983; 64: 359-370
[33] Nadar S.K., Blann A.D., Kamath S., Beevers D.G., Lip G.Y.: Platelet indexes in relation to target organ damage in high-risk hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). J. Am. Coll. Cardiol., 2004; 44: 415-422
[34] Negrev N., Ganchev T.: Influence of nonselective beta-adrenergic impacts on the effects of thrombocytopoietin in mice. Acta Physiol. Pharmacol. Bulg., 1987; 13: 35-40
[35] O'Malley T., Langhorne P., Elton R.A., Stewart C.: Platelet size in stroke patients. Stroke, 1995; 26: 995-999
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[PubMed] [Full Text HTML]
[36] Packham M.A., Mustard J.F.: The role of platelets in the development and complications of atherosclerosis. Semin. Hematol., 1986; 23: 8-26
[37] Pathansali R., Smith N., Bath P.: Altered megakaryocyte-platelet haemostatic axis in hypercholesterolaemia. Platelets, 2001; 12: 292-297
[38] Pathansali R., Smith N.M., Bath P.M.: Prothrombotic megakaryocyte and platelet changes in hypertension are reversed following treatment: a pilot study. Platelets, 2001; 12: 144-149
[39] Paulus J.M.: DNA metabolism and development of organelles in guinea-pig megakaryocytes: a combined ultrastructural, autoradiographic and cytophotometric study. Blood, 1970; 35: 298-311
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[PubMed] [Full Text PDF]
[40] Petrides P.E., Siegel F.: Thrombotic complications in essential thrombocythemia (ET): Clinical facts and biochemical riddles. Blood Cells Mol. Dis., 2006; 36: 379-384
[41] Podolak-Dawidziak M.: Development, structure and maturation of megakaryocytes. Pol. Arch. Med. Wewn., 1991; 85: 128-133
[42] Podolak-Dawidziak M.: Human megakaryocytopoiesis - normal and abnormal. Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch., 1990; 117: 237-250
[43] Rizzoni D.: Endothelial dysfunction in hypertension: fact or fantasy? J. Hypertens., 2002; 20: 1479-1481
[44] Rodgers K.E., Xiong S., Steer R., diZerega G.S.: Effect of angiotensin II on hematopoietic progenitor cell proliferation. Stem Cells, 2000; 18: 287-294
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[45] Rudzki Z., Kawa R., Okon K., Szczygiel E., Stachura J.: Objective, planimetry-based assessment of megakaryocyte histological pictures in Philadelphia-chromosome-negative chronic myeloproliferative disorders: a perspective for a valuable adjunct diagnostic tool. Virchows Arch., 2006; 448: 59-67
[46] Senaran H., Ileri M., Altinbas A., Kosar A., Yetkin E., Ozturk M., Karaaslan Y., Kirazli S.: Thrombopoietin and mean platelet volume in coronary artery disease. Clin. Cardiol., 2001; 24: 405-408
[47] Shibata H., Suzuki H., Murakami M., Sato A., Saruta T.: Angiotensin II type 1 receptor messenger RNA levels in human blood cells of patients with primary and secondary hypertension: reference to renin profile. J. Hypertens., 1994; 12: 1275-1284
[48] Skotnicki A.B., Jablonski M.J.: Thrombopoietic growth factor--thrombopoietin. Molecular and biological properties. Przegl. Lek., 1996; 53: 826-829
[49] Thibonnier M., Kilani A., Rahman M., DiBlasi T.P., Warner K., Smith M.C., Leenhardt A.F., Brouard R.: Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients. Hypertension, 1999; 34: 1293-1300
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[PubMed] [Full Text HTML] [Full Text PDF]
[50] Thiele J., Titius B.R., Kopsidis C., Fischer R.: Atypical micromegakaryocytes, promegakaryoblasts and megakaryoblasts: a critical evaluation by immunohistochemistry, cytochemistry and morphometry of bone marrow trephines in chronic myeloid leukemia and myelodysplastic syndromes. Virchows Arch. B. Cell Pathol. Incl. Mol. Pathol., 1992; 62: 275-282
[51] Thuillez C., Richard V.: Targeting endothelial dysfunction in hypertensive subjects. J. Hum. Hypertens., 2005; 19 Suppl 1: S21-S25
[52] Tschope D., Langer E., Schauseil S., Rosen P., Kaufmann L., Gries F.A.: Increased platelet volume - sign of impaired thrombopoiesis in diabetes mellitus. Klin. Wochenschr., 1989; 67: 253-259
[53] Vainchenker W., Debili N., Mouthon M.A., Wendling F.: Megakaryocytopoiesis: cellular aspects and regulation. Crit. Rev. Oncol. Hematol., 1995; 20: 165-192
[54] van der Loo B., Martin J.F.: Megakaryocytes and platelets in vascular disease. Baillieres Clin. Haematol., 1997; 10: 109-123
[55] van der Loo B., Martin J.F.: A role for changes in platelet production in the cause of acute coronary syndromes. Arterioscler. Thromb. Vasc. Biol., 1999; 19: 672-679
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[56] Willerson J.T.: Conversion from chronic to acute coronary heart disease syndromes. Role of platelets and platelet products. Tex. Heart. Inst. J., 1995; 22: 13-19
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[57] Wun T., Paglieroni T., Lachant N.A.: Physiologic concentrations of arginine vasopressin activate human platelets in vitro. Br. J. Haematol., 1996; 92: 968-972
[58] Zatz R.: A low cost tail-cuff method for the estimation of mean arterial pressure in conscious rats. Lab. Anim. Sci., 1990; 40: 198-201
[59] Zauli G., Catani L.: Human megakaryocyte biology and pathophysiology. Crit. Rev. Oncol. Hematol., 1995; 21: 135-157
[60] Zimmet J., Ravid K.: Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system. Exp. Hematol., 2000; 28: 3-16


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BFF – brand friend forever
With the world literally at our fingertips these days, consumers are free to make highly educated decisions about the products we purchase. The power of social media allows us to interact with brands like never before. Brands have almost limitless possibilities to make connections with us and we can tell them instantly whether we like them or we don't.
I saw an ad on TV recently that featured a young woman delighting in her positive pregnancy test. After sharing the news with her mate, the consensus between the two of them was – now what? That's when the voiceover suggests they visit the "Huggies Mommy Answers" website. This is a brilliant move on the part of Kimberly-Clark Corporation which recently retooled its Huggies site as part of an effort to befriend a woman as soon as she gets pregnant. As Huggies takes the journey with mom-to-be, a very real friendship develops and nine months later, a customer is born – pun intended.
Savvy advertisers are targeting consumers and becoming our friends before we even know that we'd like to buy something from them. This idea translates to B2B marketing as well. After all, a business is a collection of people, a.k.a. consumers working towards a common goal. As you enter your next marketing initiative consider how you can befriend your customers and create lifelong brand loyalty.

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What is an Apple Shaped figure?
You have a broader shoulders compared to your narrow hips. Your legs and thighs tend to be more narrow while your abdomen and chest are wider. Apple shaped women look for swim suits that will reduce the waistline and create a slimming effect.
Here are some tips that can help you choose the right swim suit for next spring break!
Tip 1
By wearing a slight V-Cut top, it will draw attention towards the bust or face. Also, bikini bottoms with accents can help make the hips look enlarged! Nicolita's Senorita Solids provides excellent support and coverage that still keeps its sexiness with a low-cut neckline. The Hipster Bottom sits low on the hips and feature Nicolita's No-Pinch Fit elastic with shirring in the middle that creates a hear-shaped backside.
Tip 2
Your top should have thick straps, which in turn will make your top half look smaller. You can do this by pairing Senorita Solids Adjusted Halter Top which also includes wider straps for more support. The Senorita Solids Boy Shorts have a heart-shaped backside to give a cheekier look.
Tip 3
By wearing a one piece with a v-neck, it will add shape to your midsection, giving it that narrowing effect. You can try the Nicolita Knotty by Night Cross One Piece. This cutie features a similar thick straps that cross at the back instead of the neck, which creates a more comfortable fit and is a great compliment to the knotted heart-shaped backside.
By following these tips, Nicolita can help you balance and accentuate the body. By portraying her Cuban roots, the designs behind Nicolita are full of flavor and always keeping the woman's body in mind. In no time you will be ready to sip your mojito pool side!
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The Parrot Black One Piece swimsuit is one swimsuit you cannot live without.
The SaveSaveSaveSave
Hola! I'm Nicolita owner & designer Nicole Di Rocco. In this video I'll show you why and how we created our signature Nicolita Bottom fit.
Nicolita has one-of-kind swimwear styles that are carefully designed to flatter your figure. Say goodbye to those ill-fitting bikini bottoms and say hello to comfort and fit!
Below are a few of our most popular styles that were designed with YOUR hips in mind.
I want to help you find the Perfect Fit Nicolita Style. Below I have created a Nicolita Swimwear Fit guide to match your curves with our swimwear options and styles. If you still have questions of which bikini or one piece style would look best with your body shape just Call 866-NICOLITA (866-642-6548) Email hola@mynicolita, or Skype me @mynicolita.
Over the last 13 years since I started Nicolita in 2003, I have worked with a lot of Nicolita clients on selecting the perfect swimsuit for them. I'm the first to admit that wearing a bikini or one piece swimsuit can be challenging for the majority of us. Even if you have a rockin' body, there are certain styles that work better on certain body shapes.
But I am a strong believer that there is the perfect swimsuit out there for you. And we have gone ahead and picked out some styles that are flattering for you!
Women with larger cup sizes are primarily looking for 2 things when trying on swimwear: coverage and support. While going up a size in the top can provide more coverage, some styles just won't provide the coverage and support you may be looking for. Look for styles with side boning and molded cups to give you the support and coverage you desire, without the pinching of an underwire!For support and coverage, check out:
Have a smaller bust and want to create the illusion of a bigger chest? Styles with details like ruffles and molded cups will add volume and create cleavage!
For adding volume to a smaller chest, check out:
Haute Dot Bow Tie Bikini Tube Top
If you're looking to tone down the appearance of broad shoulders, look for one-shoulder and detailed tops which will draw attention away from wide set shoulders. Deep V necklines will keep the attention focused on your chest and the low cut back will make your shoulders appear more narrow.
To elongate the torso, check out:
Rumba Ruffles One Shoulder Top
Looking to add more curve to that backside? Look for bottoms with backside details like ruffles, shirring, or our signature knotty bottom. These details add more curve to your bottom and create a more shapely bum.
To add curves to a not so curvy bottom, check out:
We all have those days we would rather cover our midsection. To conceal your midriff while flattering your other assets, look for styles that have shirring throughout the midsection to camouflage any insecurities.
For tummy control, check out:
Deep V One Piece With Shirring
Noche Cha Cha High-Waisted Bottoms
Trying to keep your skin out of the sun, or just desire to be more covered? Look for styles that provide more coverage without sacrificing style, like high-neck tops, high-waist bottoms, and one pieces!
For more coverage, check out:


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Get your legs into some legacy lines with the Tribong. With simplistic, refined style, the original Tribong colorblocked boardshort embodies Gordon Merchant's collision of workmanship and style. It epitomizes the classic surf short.
Outseam: 19 inch
51% cotton / 43% polyester / 6% elastane.
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Throw your email in the box and get up to speed on all things Billabong! From the latest and greatest, to product releases and promotions... Take your Billabong Canada experience to the next level!
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Listen to free music by Anjelica Huston
Blip.fm is internet radio made social. It's easy to search for, play, and discover free music recommended by real people. Join today to create your own free station.
Artists Like Anjelica Huston
Blip.fm DJs who play Anjelica Huston
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Get connected to social, health and community resources near you.
Additional Support
"Just Dads" Group
508-234-4181 x 5093Website
Statewide Resources
88AgeInfo provides information and a service directory for seniors adn caregivers in Massachusetts. The organization also provides an online needs assessment to ensure seniors find resources to match all their needs. Information is available on homecare, housing, healthcare, and employment services for seniors.
Additional Support
A Second Chance – Samaritans
Peer support group for those who have attempted suicide and survived.
AboutFace is produced by the VA's National Center for Postraumatic Stress Disorder. Here, Veterans can learn about PTSD, explore treatment options and, most importantly, hear real stories from other Veterans and their family members.
Additional Support
ACS Cancer Support Group
This group meets on the 4th Wednesday of every month from 7:00 -8:00 PM and is for those who are going through cancer, have survived cancer, or have a loved one who has fought cancer.
Counseling Support
AdCare Hospital
AdCare Hospital provides treatment for individuals affected by alcohol and drug addiction, including those with more complex psychiatric or medical needs. An additional outpatient clinic in Worcester offers intervention services, counseling, and support groups.
Counseling Support
AdCare Hospital of Worcester, Inc. Inpatient Services
Specializes in inpatient medically-managed alcohol and drug detoxification and rehabilitation treatment for adults. The levels of care offered by AdCare are inpatient medically-managed detoxification, inpatient medically-managed rehabilitation and inpatient medically-monitored residential. Accepts Medicare and most commercial insurances. 24-Hour Admission and Referral: 1-800-ALCOHOL (252- 6465).
Man Therapy is an innovative tool designed to help men with their mental health. It uses humor and media to connect men and their families to facts, resources, and help in grappling with ongoing negative emotion.LEARN MORE
Looking for a therapist or counselor to help you deal with anxiety, depression, PTSD, alcohol use or family and relationship issues? HelpPRO offers immediate access to nearby groups and therapists.FIND A THERAPIST


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Manish Datt tells me to roll the cigar between my fingers. It evens out the flavours and saves dilettantes the ignominy of having their cigar go out. I'm not supposed to ash it; instead, I'm supposed to study the construction of the long and sturdy cigar ash.
At The Cigar Store in Delhi, Datt's 10-year-old haven for cigar aficionados, everything is a ritual. And this hedonism has a small but dedicated bunch of followers in the city. In the past, Datt has organized cigar and single malt evenings for his patrons; he runs a cigar-on-wheels service and he even started something of a trend by hosting cigar counters at A-list weddings, including that of actor Elizabeth Hurley's. Datt's latest extension of the cigar culture—he feels he is its guardian angel—is through art.
Last week he hosted an exhibition of "cigar art" at a farmhouse in Gurgaon. The exhibition was the culmination of a week-long art camp held in conjunction with the Delhi-based Enigma Art Gallery. Fourteen emerging artists created canvases of cigar-inspired art, priced between Rs30,000 and Rs95,000. This was the first showing of Datt's Cigar Art Company. In April, he plans to host an art camp with senior artists in Cuba and other parts of Latin America where cigars are rolled.
At The Cigar Store, a heady fragrance of matured tobacco leaves, somewhat musty, somewhat woody, hits you even before you light your first cigar. The glass-walled humidor showcases Cohibas, Trinidads, Montecristos and Romeo y Julietas priced at Rs200-2,000 each. Datt also has 15 private cigar lockers for patrons who wish nothing less than professional care for their prized possessions.
We're smoking Trinidads, an ultra-exclusive brand that only the Cuban revolutionary Fidel Castro was authorized to hand out as diplomatic gifts. Datt recreates this intended exclusivity in the store. Elaborate cigar paraphernalia surrounds us: cigar cutters, long elegant matches, leather pouches and cases.
Rolled up: Datt (foreground) with artists at the cigar art camp in Gurgaon last week. Priyanka Parashar / Mint
"Aficionados in India are building cigar lounges and bars in their homes now. They stock the choicest of cigars sourced from all over the world," says Datt. However, he confesses that the ban on smoking in public places has taken a toll on the cigar market, which was growing at a phenomenal pace of 40% annually. His venture into the art world is an extension of "brand cigar", which can be read as something of a subliminal marketing tool geared for the sophisticate. He hopes the Cigar Art Company will draw more people to the world of cigars. "Wine, whisky, cigar, art...they're all different facets of the good life," he says.
The rituals are endless. But an important one to remember is to twirl the cigar smoke in your mouth much like whisky, and never to inhale. Those cigar headaches that give the rolls a bad name are caused by the alkalinity of the washed-out tobacco that cigars typically use.
When I'm done with the Trinidad, Datt asks me to lay it to rest so that it smoulders and dies on its own accord. Stubbing out a cigar, you see, is blasphemy.
You can enjoy the olfactory sensation of Cuban tobacco leaves at 15, Santushti, Race Course Road, New Delhi. For details, log on to www.thecigarshop.in
Photographs by Priyanka Parashar / Mint


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Tummy Tuck in Bloomington, IL
A tummy tuck (abdominoplasty) flattens the abdomen by removing excess fat and skin, while at the same time tightening the muscles of the abdominal wall, restoring a firm and toned appearance often unachievable through diet and exercise alone. The surgery is particularly relevant to women who have recently undergone pregnancy, or individuals with excess abdominal skin due to drastic weight loss. A tummy tuck, however, is not an alternative to losing weight through diet and exercise.
How is a Tummy Tuck performed?
Full & Mini Tummy Tuck
There are two types of abdominoplasty procedures – mini and full. A mini tummy tuck is performed if the patient's treatment area is confined to the lower abdomen. This procedure carries the benefit of not generally necessitating the repositioning of the belly button. Less surgically extensive, it also allows for a shorter recovery period and a smaller scar.
Loose muscle, skin, and excess fat throughout the entire abdomen often require a full tummy tuck. The increased scarring associated with a full tummy tuck is offset by the greater improvements associated with the procedure. During the pre-surgical consultation with one of our board-certified plastic surgeons, they will help to determine which procedure is best suited for your needs.
During surgery, a horizontal incision is placed just within or above the pubic area, the length of which is dependent upon the amount of skin being removed. For those who have recently lost a large amount of weight, a smaller, vertical incision may also be employed (to correct horizontal skin laxity). In addition, areas of fat are treated with liposuction, while the skin is stretched to tighten the abdominal area. Muscles within the abdomen are also tightened using sutures in the lower midline.
After surgery, a drain is placed in an incision point to prevent the buildup of tissue fluid, which will be in place for up to 6-10 days. Depending on the extent of the procedure (such as mini vs. full tummy tuck), tummy tuck patients can expect to return to normal activity from between two to four weeks following surgery.


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Get Pet Questions Answered by Pet Experts
I have a 6yr. Old rat terrier who I took to regular vet
I have a 6yr. Old rat terrier who I took to regular vet today for rabies and "yearly" corona, parvo and DHLP vaccines. Also had lab work prior to having teeth cleaned. Was told red blood cells moderately low (in 20's level). All other labs normal. So vet rechecked x3 times with no change. Redrew blood to send to higher level lab. My concern is I told vet of my dog having recently demonstrating weird symptoms i.e.: shivering at times, hypervigilant, lethargic, and loss of appetite. Vet told me it could be anxiety, age changes in brain etc. I came home and googled dogs symptoms and discovered many reports of same symptoms and more all possibly related to trifexis which my dog receives. I should get lab results tomorrow... I read all of the different types of anemia in dogs and became very concerned. Is there any cure or antidote for this type reaction. I read of one dogs owner being told by a Holistic vet to give liquid dandelion and liquid milk thistle which gave good results. Any help, suggestions, or recommendations would be very appreciated. Sincerely, ***** ***** XXX XXX XXXX or XXX XXX XXXX XXXXXXXXXXXXXXXXXX I am happy to pay for services.
Hello and welcome, Virginia. My name is ***** ***** I'm a biologist with a special interest in canine health. I have used holistic medicine with my own dogs for many years. I'm sorry to hear about this problem.
The most serious of these symptoms you are seeing is the anemia. Trifexis has been linked to immune mediated hemolytic anemia, which is what I suspect you read about. No studies have been done on it, and no statistics are kept on the incidences of certain diseases in pets, but IMHA is considered fairly common. We do know that certain breeds are more prone to it, and that it occurs more often in middle-aged and older dogs, and more often in females. Some studies indicate that it may be more likely in dogs with certain blood types. There are several different causes - some cases are genetic, some are a symptom of certain types of cancer, toxins can cause IMHA, modified live virus vaccines have been linked to it, and so have certain antibiotics and heartworm preventatives (including Trifexis). The following links have more information on IMHA, including which dog breeds are prone to it.
This one includes a list of possible treatments, and all the etsts needed for a positive diagnosis:
There is no official antidote for Trifexis. The dandelion and milk thistle you read about can help the body clear itself of toxins. I would discontinue the Trifexis, and go ahead and give those herbal remedies. When the drug is cleared from your dog's body, those other symptoms should diminish, but if your dog has IMHA, these measures will not be enough. Corticosteroids are usually the first line of treatment. I had a dog several years ago who developed IMHA. He was treated with steroids, and I gave him iron-rich foods. We were able to reverse the anemia. It is not always fatal.
I know you are worried, but at this point, we can't be sure your dog has IMHA. There are many other types of anemia. Further testing is needed. It's possible your vet ordered some of those tests, so you may know more tomorrow. My first recommendation to you would be to get a second opinion. Be sure to tell this vet all the symptoms and your concerns about Trifexis. However, I'll warn you that most vets (other than holistic ones) are very hesitant to blame a medication for anything. Regardless, it's your decision about what kind of heartworm preventative you use. The older ones, such as Interceptor, are tried and true.
If you would like to see a holistic vet, this site has a directory of them. Just click on the "Find a Vet" tab at the top:
In summary, I would discontinue Trifexis (it will stay in his system for about 30 days), consider the dandelion and milk thistle, and get a second opinion. If you have more questions, let me know in a REPLY. I hope your dog will be fine.
My goal is to provide you with excellent service – if you feel you have gotten anything less, please reply back, I am happy to address follow-up questions. Please remember to rate my service only after you have all the information you need. Thank you!


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Keynes is back - the refugees brought him!
Peo Hansen has written a piece for the web journal "Discover Society" which argues that EU's dual and paradoxical approach to mogration, asking for more migration, and less, simultaneously - might carry a Keynesian solution in it midst - if we only put the two policy lines together.
In the article "How the Refugees Smuggled Keynes Back from his Exile", Peo Hansen describes the paradoxical policy positions EU sine quite some time have been occupying. One the one hand, EU has done everything they can to keep refugees out, on the other hand they have opened up for and explicitly called for the great need Europe has of labour migration, with reference to the well known demographic crisis.
Hansen argues, with the notion of, "refugee keynesianism", that by putting the two together we could imagine a slotuin appearing in which the refugees now coming to Europe will take care of a part of EU:s foreseeable labour shortage. An important obstacle for this, however, is the long-standing committment to an austere policy on economics as opposed to a "keynesian" approach seeking to stimulate production through public investment and thereby stimulate employment and thus consumption, which in turn creates growth.
Read Peo Hansens article here
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Last updated: Sun May 15 18:28:36 CEST 2016


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Just For You, Dad
Father's Day is on its way! Personally, we love personalized gifts.
Dads do too, right? That's part of why they love the little handprints kids bring home from art class, or the tiny clay pots they make. Not only are those trinkets darn cute, but they represent more than a little forethought: "I made this just for you, Dad!"
Here are some other gifts that get the same warm message across, albeit in a more grown-up way.
Check out this personalized bottle opener. It's the size of a credit card to fit right in his wallet, and you can put any message on it you'd like, from "Here's to you, Dad!" (get it?) to the oldie-but-goody standby, "I love you, Dad."
Here's a gift that's about as personalized as you can get (or give); a personalized bobblehead. What a great idea. (Although we will say, the company's sample already looks a lot like a few dads we know.)
Cards can be personalized, too, and not just with the signature. Here's a decoder card that can send him a secret message. Very cool.
Finally, don't forget our favorite gift: personalized art. It's on sale here at www.oopsydaisy.com between now and Father's Day (how convenient!). Think outside the box on this one: how about a growth chart that says "Dad's Little Girl," or an alphabet print that says "D is for Dad?" These would be especially adorable in the nursery or as a gift for a new dad.
Don't let the day go by without telling him how terrific he is. Happy Father's Day, everyone!


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Katie Snyder is a 2017 TU graduate from Des Moines, Iowa. She graduated with a degree in Media Studies and recently accepted a position with JNA Advertising in Overland Park, Kan. Katie Snyder does not wait for opportunity; she creates... MORE
My Take on TU: More Than One Hashtag
TU is many different things to many different people. Because of this, it would be hard to select just one hashtag to capture what campus life is all about. Find out for yourself by watching the video below. What will your... MORE
My Take on TU: 5 Ways I Get Involved on Campus
Today's blog post is written by Erin Jones, a junior Communication and Spanish major from Bemidji, Minn. BAND The music program is one of my favorite things about TU! There are so many wonderful opportunities to learn music, strengthen your... MORE


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Thanks to the frantic pace of the digital age, the average person has the attention span of a goldfish. (No, seriously. This is a fact supported by an actual study.) Seeing as the fashion sphere changes its mind even faster, we decided to provide you with a condensed report from backstage this season. As much as we'd like to pen novels in the name of lipstick and hairspray, we get it—you're busy. Here, the beauty version of CliffsNotes (all facts, no fluff) that you can easily skim in eight seconds...because science says that's all the time you have.
SHOW: Creatures of the Wind
CITY: New York
KEY PLAYERS: Makeup Artist Mark Carrasquillo, Hairstylist Holli Smith
THE LOOK: Marlene Dietrich meets dirty hippie.
INSPO: 1930s masculine glamour and "'70s cult weirdness," said Smith. "We're keeping the girl really raw to make her feel like somebody you know nowadays. Just good skin—that's what everyone's chasing," added Carrasquillo. "She's a cool girl who doesn't want to trick herself out too much."
BEAUTY MVPs: Bumble and bumble Thickening Hairspray, NARS Matte Eyeshadow in Bali and Coconut Grove on brows, NARS Audacious Mascara on brows.
TOP TIPS: The dirty strands may look "like do-it-yourself, but of course, it takes a little work," admitted Smith. To recreate the effect, douse your part line with Bumble and bumble Thickening Hairspray, applying less and less until you reach your ends. "We want it to feel grounded. I don't want volume at all," she noted.
For a dramatic twist on today's fresh faces, follow Carrasquillo's example: "The illusion is that the brow is thinner," the pro explained of models' extended arches. The face painter bumped up the beginning of brows with a bit of mascara, wiping the wand off and brushing the hairs up. Then, he applied eyeshadow from the arch's highest point to round it off, extending the tail with the same powder. "It's very clean makeup, but then there's this little tweak to it."
WORDS FROM THE WISE: Work with what you have seems to be the word of the season. Given the diverse casting, both Smith and Carrasquillo played up each girl's natural texture and brow shape. "You're taking your own haircut and shaping it around the edges," said Smith. In the makeup department, Carrasquillo kept the skin relatively untouched (save for some moisturizer and foundation), relying on the dramatic brow for a bit of interest. "It's really real to each girl's eyebrow shape, trying to push it in that [1930s round] direction without looking stamped on," he said. "The gesture is there, but it's subtle."
TREND TALLY: Slick, unkempt hair was also seen at Chromat and Thakoon, while fresh faces were spotted at Calvin Klein, Lacoste, Adam Selman, and Brock Collection.
Photo: Courtesy of NARS
Photo: Courtesy of NARS


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Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. In this review, Vogelstein at el. summarize what has been learned about cancer genomes from these sequencing studies and what this information has taught us about cancer biology and future cancer management strategies. Some key points of
Posts Categorized / Review
In silico analysis of missense substitutions using sequence-alignment based methods
Computational classifiers classify missense substitutions as pathogenetic or neutral based on inferences from evolutionary conservation using protein multiple sequence alignments (PMSAs) of the gene of interest (and other features). In this review, Tavtigian et al. make suggestions with respect to the important aspects of creating PMSAs that are informative for classification (and more). In using
Congruency in the prediction of pathogenic missense mutations: state-of-the-art web-based tools
Deep sequencing initiatives are identified a remarkable quantity of single nucleotide polymorphisms yet only approximately half are nonsynonymous amino acid substitutions that could potentially affect protein function. A confusing array of tools are available to help identify the few gene-coding variants that actually cause or confer susceptibility to disease. In this brief, Castellana and Mazza


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WMF Coffee Machines
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The WMF espresso bridges two worlds. It automatically prepares handmade coffee. It hisses and steams like a traditional portafilter, and yet is child's play to operate: for anyone wanting to prepare the perfect espresso. Because the WMF espresso automatically grinds and tamps the coffee inside the portafilter, controlling both the flow and temperature of the brew.Details
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Since we like to provide our customers with the perfect, tailored cut, they delight in their new look and are satisfied. However, unlocking this exceptional, one hundred percent feel-good smile requires that extra something. When you press the start button on the WMF 1200S – the entry-level machine to the professional coffee business – you are of course also serving the perfect cup of coffee.Details
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The WMF 5000S makes premium coffee – and indeed faster. This is because the machine benefits from a high-performance brewer that is generally only used in large coffee machines. And yet astonishingly, it requires the space of comparatively smaller models. Meanwhile, the newly developed Dynamic Milk System ensures consistently top quality coffee, along with an abundant array of specialities.Details
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Introducing the WMF 8000S: our premium class fully automatic machine. This professional machine combines innovation with personalised indulgence like no other. Its inexhaustible power delivers an extremely wide range of beverages. Moreover, it is able to adapt to the most demanding work locations and can be customised to specific hotel and catering features.Details
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The WMF 1200F makes the best-tasting filter coffee because it is brewed directly from freshly ground beans. The exquisite fragrance of freshly ground and brewed coffee – that unmistakeable aroma – breathes fresh life into any breakfast room, any meeting, or indeed, any conceivable social setting. The WMF 1200 F is the supply station that freshly grinds and brews coffee, ensuring intense indulgence, while maintaining maximum output.Details
WMF CombiNation F - up to 500 cups/hour
The WMF combiNation F is an all-round specialist when it comes to that excellent cup of coffee that needs to be produced in large quantities, over and over again. It is the ultimate high-performance, fully automatic machine in the filter coffee sector, and moreover, one of the most attractive machines currently around.Details


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Tommy Lee Jones "JFK" Costume Shirt. A custom-made ivory-colored shirt worn by actor Tommy Lee Jones in Oliver Stone's 1991 ...Click the image to load the highest resolution version.
DescriptionTommy Lee Jones "JFK" Costume Shirt. A custom-made ivory-colored shirt worn by actor Tommy Lee Jones in Oliver Stone's 1991 historical drama "JFK". The shirt has the initials "TLJ" sewn into the collar, along with the date May 1991. In fine condition.
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Business Development
We like to call this "low hanging fruit". One of the easiest ways to capture new revenue is finding other organizations that are already selling to your prospective client base, but selling a different "no conflict" service or product. By forging a relationship with this type of Partner, you can accelerate the "runway-to-revenue" by exploiting their current client relationships.
IAMVenture offers the following services:
- Partner Prospecting – IAMVenture will find, vet & close Organizational relationships to put into your Partner Channel.
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Category Archives: Patron
Coach and Horses, Clapham North
Posted on April 28, 2017 by goantolondon
The Coach and Horses is tucked away on a quiet sidestreet in between Brixton and Clapham. They have a nice outside area so if spring ever decides to return it would be a lovely place for a drink in the … Continue reading →
Posted in Amy Franklin PR, Brixton, chocolate, cocktails, Coffee, Desserts, Donuts, England, FODMAP, FODMAP diet, Gluten-Free, Italian, Ketel One, London, menus and prices, Modern British, Patron, Patron Xo Cafe, Pork, Pubs, Style of cooking, Vodka, whisky | Tagged #dessert, #DiscoverYourLondon, #foodbloggers, #FrontierPubs, #londonisopen, #patronxocafe, @CoachHorsesSW4, @DeterminedDiner, @ketelone, @TastyComms, @TastyToursLDN, @The_Foodie_Feed, Brixton, Chocolate, Clapham, Clapham North, Clapham Park Road, Coach and Horses, cocktails, coffee, cognac, dessert pizza, desserts, donuts, doughnuts, Feeding Franklin, FeedingFranklin, fodmap, FODMAP diet, food, gastropub, gluten free, italian, Ketel One, London, modern british, Patron, Patron Xo Cafe, pizza, Pizza Oven, pork, pubs, restaurants, South London, Tasty Comms, Tasty Tours London, Vodka, whisky | Leave a comment
Chateau Marmot Brunch
Posted on March 5, 2014 by goantolondon
We walked through the Lower Marsh market to the pop-up of Chateau Marmot, run in partnership with Lower Marsh Saturday Market/ Waterloo Quarter, located in Cooper's – a vacant shop now used as a pop-up space, and were warmly welcomed … Continue reading →
Posted in Chateau Marmot, Chateau Marmot by Theo Cooper, chillies, chocolate, Cocktail Masterclasses, cocktails, Coffee, Japanese, london, Lower Marsh Market, Markets, menus and prices, New launches, Patron, Pop-Ups, Sarah Harrison PR, seafood, use of modern ingredients, Waterloo, Waterloo | Tagged Chateau Marmot, London, Lower Marsh, market, Patron, pop-up, Rittenhouse Rye, Sarah Harrison PR, The Pressery, waterloo, Waterloo Quarter | 2 Comments